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

by

l4ajor James S. Ketchum

Pro ject Itluntcer: 1R5)+3603D016- o2

Titl-e of Project: BZ Weapons Systems,
Med"ical Aspects

Actg DirecLor of Nledica.I Rescarclt

Htrman fnvest:lgati ons Fa.ci.i,lty

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ilirecborate of lviedicaf
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U. $. Arrqy Chen-ica.l Research and Development Laboratories
Fdgevood Arsenal, Maryland
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iirt. Ii(, ]'r,[ii'l'y 0t'U. S. ARMY

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I,ABORATONIES
i BRARY
AAMY CIIEMICAI CENTEN
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I. GMIMAL I]'JTROIIJCTTOIJ I
]r. HUMAJ.{ II"I,AR},IAC OIOGY ?

A. Gcneral" 3
D
Carcll o circuJ-atory tr\rnetr on )1

c. Ga stroin'ce stinal f,\.urcti r:n. )r

D. Gtnitourinary. 6
E. Skin . b
r. Liver anrL 0bher &letabolic !'unctions. . 6
G. Central Nerwous Syctem. T

1. General. 1
D Scnsory Function. o
J
J. l,lotor Activity. a
),
Homeostatic Systems ]l-
r I{igher Integrati.,'e f,'lrnc-bions. 1l_

III. ]TVAW.ATIOI{ OF I'CPI]R[I,M]A'AI, DATA 20

A. Dose-Ilesponse Rel.ationships . . 20

1. Tota-L Rcsponle Inclcx. lv

2, Belative Dff'ectiveness b;,' Various Boutes. . 25
3. Estirntes of fneapaeitating and Lctat Doscs . 30
);. Rcsponse lo Repcated. li:qrosure .
5. Tcqroral Response Characteristies . . Jo
6. I'bclification of Response by Treatment Ii0

B. Studies ol' j'i,il-itary Perforr,:nce. 44

t. Indlli.clual Perf or"u:e.rrce. 4l+

2, Group Ps:fonnzr,nce \5
IV. MILfI'/lIff I\frlDfCAI CONSIDLAATIOI'IS )+g

A. Hf'fectiveness and Saf'o1;y" t+g

I. Variatlons in Dosagc. Lv9

a. Variatj.onc in Susceptiblllty. t+g
?
J. Factors Infl-ucncing l4ortal-ity 50
l+. l,Itlltar:r Fac'r;ors 50

B. Ih.nagement of Casualties. 5L

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rv. LITERATURE CITM qt

APPEI{DTXES

A: Design and- Methodologg

B. Chemlstry and, Slochernlstry af BZ

C. Flgures and. Tables

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TWFIDEMS.N,AL

(u)

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 gave
lnvaluable ossistance in the clccign of crperiments, crpcrlitcd" tlrc
acquisitibn of ncccssary portouncl ancl. equ-ipmcnt, a.ncl participatcd
aciively 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 of
BZ 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 chcinistry
and biochemstry o! M, appears irr thc appcndl-.( cf this report.
"rnich
!'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' of
ToxicoJ-ogy D-vision; Ih:. Chnr'les Punte, Chief of' Aerosol Brancir of the
To:'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 the

obscrwatlon 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 to
the niethoclol.o3y of audio-visua1 ctocumcntu.liorr ancl presentatlon of
exPerimental data, Itir. Lloyd" I,lattc'::, cnginecr in chargc of the Meclical
Tel-evislon Facility.
For thcir d.cpendable and conscientious perfor"nance in thc
area of
perjJorrnance testing and assessment, sP-5 Alan Morror,i and
SP-5 Ephrajm Gooclrnan. For :llraginativc and dillger:t assistance in the
developmcnt of unique 'best instrunents, and in organizing and. preparing

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effect.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 essential
to 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 nurscs
assigned to this Facility. Par.bicr"rfar gratitucle is expressed. to
l,irs. Frances E. Peck, l4rs. rlunice !'ort, FLrs. June J. A. Brenneruzn, ancl
l"lrs. Jane King for the cor-ntless snall r,rays in r.rhich, thrcugh their
ipitiative, tlr.e quatrty of volunteer care ancl ilre con4rleteness of
experimental protocofs have been enhi:.nccci. A1 so creserving of' recognition
isthe d"evot,ecl serwice rcnd,crecl by tl're f'<t-L-lor.ring nurscs, wiro scrvecl for
shorter 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-rn
of 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.c
servicesr"Miss Pat Ross, I{rs. nlsie lleucr, ancl Mrrs. Joanne Ileverati.

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(c) Tiii:l ]{U}"l.itl{ ASslLssltrli,ru r',' AGi:jll"l lZ (U)

., A Sta.'tus Summary
I

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

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

vithjn thc llurrurn Invcsti.gatjons lracility, Direct,olaLe of' }.,Ierlica.l

cor:d.ucted
-^ 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::rilng
tlle 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,c
r' 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 of
a 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;r
each of 'circ prirrcipl.c ::oul,es l.ret:e jnitjated. The ca.sc lj sl has bcen
contj.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.,
I '' 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 such
cstinnLcs 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 systernt
of 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, .inclucling

onset 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,erm
rt an il ,.
c1 lCCLtVC. e

I
5. Tite eflcct of nultiplc daily e)q)osulres 1;o .Low cl-oses
ol'the agent, attd thc amount that may be tclcratccl urrrler l,hese cond-itions
r'ri'bhout cuniul.ative cffects
6. Tire effect oll a, second er.posure 2 to lr rreclis f'o-Llolrfng
an lnitial- e:cposurc to the agent
(U) Ii':.1'onnatj-on of a lcsser orclc:r: of cclta.inty is al.so presenr,ecl
in 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

a
pcrfonnancc.

?. f'or i,he a.gen't a.nd {'ac-br:rs

Est-imatcd I-,D valucs LD
"'//Lt Lv'E-
mi,ghl, br-. c,.rrpc-.c't,cd. to a-lter tffiF-ffinrates in var-i.ous situa'r,ions #a"
populations "

3. Thc status o{' the::apy and rccommcncrecl procccl.ures in

the 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;ccl
r.,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 been
f'a.clljtatcd" greatl:l, anri in s<;rnc ca.scs in:'t:i.ated, by thc rescarch activlty
of members of'thc foxico.Logy Div:Lsion,the Physiol-ogy D-Lvision, and" iire
ii;'Ferirnenta.-r l{rrrir:irt;,: i.r'is,istr. Thc Psycho}ogy and llurnrr.r lrr,ctors Ilngineer-
.1.;

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:ught
about by IV' and o'Lher psychochernlca.ls, ancl a consiclerable portlon of'the
data prescn'tecl in"btris report lras gathercd ori5;inally'by mernbcrs of that
tlranch. 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 sheci
frora 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.opment
La,boratori es .

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\v/ 'i'her:e are, hor'rever, rliiferencr-',, ,,rno43 thesc compouuds iir one
, -_* '-;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
r.'' 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,
s rcqui red to pi'o.J,uce sign:if i cant d.i stu-r'[ir]cei i n
Lj.

' ---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 attribttte
of 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-nerl
a.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 ntuch
a more 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 rnore
than ncadcmic jnterest. I'b may, :f'or e;<a.mple, cnl,er jnt;o 1,he est,:i matj-on
oil 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
-ani1 ccnsister,tly r>bcerrrerl r,rhen closes r.?-;ove L+ yt:lt,g
are gjven va.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 up
to, br.lt rarely e;rcoecljr1g, l-5O l:eil'bs per ninul,e a,re often atta.,ined a.b the t"
peah (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 from
e:cerci se alone. I'lo ser-icus abnor-ma,hti es hs,ve been seen in I.liG i,raci-ngs
f'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

(c) Bltloi! -Ilrqssure , botli s.ys-Loli.c ancl dl asloli c, i s e]-ev,r.tcil

. -mo<leratplyr+d-ti1 1rcak 1-q.lues at 5-5 hours. Va,rues exceecl-lng t6O/ffO
are u-nusu.a.l, even dr-rrjng severe reactions, PreoumaliJy thc l-rl,.oocl Dressure
el.evation j-s large1 y a secol-rd-er.ry consequence of 't,tre jncreased card.ja.c i
orr-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
,t?.qi.r.:;F sl'-in aieas, is a-core.*i-s.!--qnb -.ocqqqrel-rce. J1, is proba}.lly -t'/
"o],her
clue 'Lo several l"rrtononricJaci;,r:;rui:#j.:-?:*:l_":Hllary tonr:, iucrease

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jn bl,ood prcssltl:e, reflex d;la. l,al,tot'r !rs a comlJensa.',,c,rry heal- loss
a.ni1
mechan.' 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,ieularly jn the 1egs, is a f'requent
,::rmplaint., -ac]u41 nrusjJgi;.l1reng!n i s o1l;.r minJmally clecreasec-l (as strom
i;.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 upper
i,,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' -Zorl in bod-y-i.empera.ture is iyp1 cal clu-rln1

,1

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 loss
mechanisms, 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 ng
of the mueou.s membra:res of the mou1,h. and tiiroat, and. ma::ked pharlnrlleal
d.-i scodorb. Sr,ra.l-i,:wing may be pa.inf'r.r1., ancl speecir may be recluced 'to a
vhisper. 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 urglng
Peristalsls is subdrred, bu1, comple1,e absence of Lror,re} sounds i 'l.y' s unconrnon.
'l-ru.i,
l[1lcl consi,j pat i on s .frequent r
j. nornra l iiorre]. functi on sttal
t: 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-aL
rrlro 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-is
time 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.csjrc
t.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 rcstricteci
on thc clay of cr';Ix)sllre rmcl bladclcr ?eLcnl;j.r:u tloco t'to'L ge:tera.J-l.y rca"cir
cxireme 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 :;alcl
rega.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 lrcrc
foll-or.recl -i ri one jnclivirlual crqrosccl Lr:'(.0 prg/hg im. Motl-c;'aLc e l.cvation
to 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.r
injuril, 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.rrn
s'cudies havc bccn r.ni t,hin nor-rurl- l.i.tit-i'bs.

tilrl;i"l's$i$
 CONFITIffi"{:IAAI\ UT t LLD: - [;iifrg.A$$iffl
G. (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,ling
nol,iccabLc a,u ai-.or.t.l, onr: hor.rr. T,a.r),,r, ccirl,ra]- ItcrvouI] l;ys,ucm natril'csLa- i
t-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 .
(C) Drri.ng'tirc f-i,rs'c phrsc (l-ll hours), Ci scotnf'orb and app.rc.-
hcnsi.on arc nrarlicel . JJ;<Lr,cnc rcs-c,,.l c[ir]ncss occitrs r'rLltli i nrro,L,rur i.,R.rli c l r)tri. c
spa$ns or' 'L,hc e;:Lrcrn-L 1. j cs arrcl b-i ::c.l il.,c {'i apping oL' thc ol"lx.r;. I 'xti's cI'
a' spcech atri-1. sc:r"1', l,cl'ccl, t:Lcltcit"l,s ol coniul'ioLt rii:r-' trc nOL,^cl . .A.t'l:r,T a Cf()J-
c i':nd.o of rc: s i s si_r. c s: s encl a'i;a:;i c., a i,c:c'): r nl L:' c - (!-f a hor.',1is) 1;cgj ns.
-'1. c-'
"

(c) Lhr-Lltg tnj-c secrrnrl ph"rsc, scdir-t.i on, sLupr:r a;rr.i cvcn r,rcnj c()liL:l
c1.cvc1,op. Ti.c i-nciiv:i clr-ia-l s1-ccps ot- nppcars i,; slccir anci r:spcncls on,L ;r
i,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, .;no
through a-l,j- ei- '',oc-1,cs . As birj. s prinri'l,i.vc behtl-.i.cr, rcr:lii:i rr;cn1; oi t,hc
d.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,crs
e lir.irrl- lilr.,:c (bcgiruring at 12 hor.rrs) cLr,rring rrirlch-Lht,: nor.c spccta,cular
slmptoits C.c."-clop

(C) As sr:ccclt rc1;u"trts it is in c-r-iplcci-, llnl acccirLr;, c,;,i1,a,inir:il

r: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-.ry
comron.

(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 ;, iglorcrl
or 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 flrirst
are Icss l,han ur:u,a-l-. Thc subjccl, ircgirr.r 1,o responcL to shor'l-, i-nstrrrctions
a,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' his
allnoyancc. 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. Llru
'- 'ad

-** t]l;iltfi$$!f,rEil
F -----
i'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
'Lir r-tsc thc Lat,rinc,
1;'\ hc ilaJr s'r"""ccL in convclling some rri.sh, such as a. clesirc
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 is
poisoncc.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 rclrarlis
about "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:ep
g;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) flcnsor,," Iu:rc'ti.on

(c) lJv-i.d.encc fcr actua,l sene,cry ,Loss :is rat,Lrcr l.na.r1cqira,Lc, sj.ncc
nrost 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 numbness
thronghout 1,Ire body"
(c) tr,tren .l-nca.llacl.tating rloses arc givct-r, sc)iTle loss of' scnscry
acuity appcars bo clr:vcl,op 1n all mocial.i-1,1,es, togct,hcr vr:i-1,h inc::c-a.sing
clouding of conscj (-\Llsness, iLizzinecs, clumsincss, and rcsi,l-ciilncss. The
peak of this; ocnso::y j,mpalr-mcrtt is 6encra.lly rca.ched ltithin si>l hours
and 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

f
 pick up small- ar.bicl:s, real- or
'o.
feedi:ack of light 1;oLicit and pressure tii.; facj-litates 1,he spatial 1':rcali-
:::tlu
rl[[

zation and gripping of srnall i'l,ems vitir tire fingcr tips.

I --
(c) D:finite loss of acuity for near vision has been demoustratecl
-1.'oll"owj-ng dosr--ssufficierrt, to procluce moclerate or sevcre rr3$ponscs.
'i'ilis, howevcr, $ecuis 'Lo be main-ly du,e "bo "bhe paralysls of itccr,urriioilaLjon
that results frlrn tire action of the agent on rnuscle f:'.bers control-ljng
the convexity of' the lens. Mcasurement of abso-Lu-te vjsual tirrcshold has
not bcen perfr:rmed, bul, color vis:ion discrinrinatjon has been l,est,e,l, ancl
shows 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 been /'
measured. a,t scvera-L dose levels arrct, although some ques{,:'-ons concern-ing
the 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 of
the capacity to cor:perate in any test prrrccriurc. rmprovement in acuity
seema 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 is
essen-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.cLrugged
personnel uho a.rr: r,/ith tirem. One ort vo ind.ivicluals ha.rre thor-rght "i:heir
hands lrere blceding',ihen r.raslring them uncler the'uap. l.ihct-,her1,his is an
optlcal phenomenon relatec in sonc r.'air to engorgernent of rct:inal- bloocj
vessels 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:,. .i,:nons.t,ratr.,c1
r,

in 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 EDIO
dose. Thls may be fol l.owed by feelings o1't-ightness of the muscles ancl
an uncomfortable se-'nsation of wanling'bo move about and- "get rid of ilre
tension." A perlocl r>f squirn'ing ancl thrashlng about ln a tonnent o1' t/
rcstl.essness sometincs culrui,natcs t,his sequence, after r^'hjch the subjec'u
finally becomes quieter and. lapse s into a. stupor^ous or scrnj.-cema.tose
state. The clecp tenrJ.on ref"lexes c).uring this phase are progressivel.y
increasing in the ror,ier ext::ernibies, rnrith littte change in the uppcr.

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

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-CONF.IDENTIAL- -.
 ut{fiLh$$iFlEB
Superficial abclotlinal ref.l-cxe s ar rcr
' , 1,i
ronus may bs
observecl. at l+-5 ]rours, a.cconpani I - ^r nnr,
ulvlrar, rrf r-u-+..,l'al
^ w\ lebi:ts]i.i
s-i"gns, an(i ot,hcr palho-Logical rcsponscs .,., cil as oosr-tive Hoi'i'm,enn, €irs.sp
and cven snou-r rcf'lexes.
(c) Definite -inpairrnent in cr:orclinarion, rapid a-l-l,crnaiing novcments,
of distances, valking, articu-lai,ion oj.' speccit, lrrit.i.ng, and
':r,r,rLging
dravin3 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;cncnts
in 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-t
perj-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 by
a 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. period
of 2-L hours. llne thiriL phasc, r,rli-ich bcgins at 8-ta hours, is again ouc
of excitatlon and hyperactivit.,', starting vlL,h gr,:pi.ng and- prini'Live
scarching 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-\8
hours of const,a.nl ciisoi'ganized sea::ching, warrderi.ng, rnn"nipulaLj ng, rective
activii,y accompa:ried by inccssant ta.lking, -lauglring, occesional shouting
or r:ursj-r:I!, and }:ricf disp-lays ol' irrita.bility, cometimes lnterspersed
wj-th an-iable or even a.iiiorous bchavior 'colrard nurses, j-echnj-cj"&nsr an
ad,jaceni; volunteei: srib;j ect, the physicia,n, a pillow, a TV ira.ssock, or i,hc
water 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 slecp
a,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-tstion
supe.r'ven()s, it is prece,lcrl by a trra,dual re1,arda'uion wlbh brlef , grai,uall-y
lengthening pcriods of quietr-rcle bebr,reen shorber and shorter bursts of
suclden activity, rabher like e. rrincl-up nechanj.cal toy twitching convulsively
as 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'tcr
one or tlro alrairenings during wlr.,l-ch foocl. nay be takcn arrd, e>:cretory nt:r:ds
attended t,o, a J-ongcr period of'ver;y Ceep slcc:p general-l). occu,rs foflor+ed
by rnrkecl improvcment leading to f'ull recovcry over the succecdlng da:l
or tr.lo.

n.n: l. r rglgltw
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(c) Wibh sr,.tall cioses oI'M, exclta ,;rn is somei,irres noi; scen at
a-l-I, or is ve::y rdl-d and transienL. fn;) ,,'-lcl, sedation 1s'i,hc precloruinanl
effect, and. j L is not unconrnicn for subjccLs receivlng closcs bc1,wcen ll
and ! 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:sent
or 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;ions

of 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 thc
braj.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
a' .referreC tc zs the linrbic system. The obscrveri, in1'1uencc of the aga.rl
on 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 such
clusirtc construcl,s asj "motivatlon" ancl "attenLlon spiin" suggesl;s strongly
that 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 lire
demonstration 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 reccnt
Itork on the netrrttanatomica.l. ancl neurophysiotogical corrcl-ates c;f' learrLing
suggcsj';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'ortletl
lly varlouLs rcticul-ar netvorks. tr'/hcn clisruption of these occursj, norrnal
cerebration 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's
rccognitj-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 the
reacLlr;n. Because onets l.ocus in tirnc changes coLrtinr-rally, this climension
of orientation can bc bcstecl repea'l,cc1l_y.
(C) Frcquclnt-l-y, Llmc ":tandn lt,:i. ll." Jlr'lr't,he incapacl'-tated upb,JccL
from somct1rlc t>tr t,he I'i::st rlny unt-.:il ncarly cornpleLe rccovery 2 or J <Jayc
later. At thai, tlme hc rnay thi nI< 1t is st,ilJ- the clay on which he receive<l
the drug, somctimes in the face of extcrnal eviclence to the conbrary.

u,- -,-- -,,-

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CONFffiESJ-I
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i '
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[}ffi$tfr$$ErlE$
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-'bhc
For: exanple, onc pa.lt corraenbcd on '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';n an
!

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. Qaestions
that 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 stlcet
fron lhe NCO cr.ubr etc., even though he has just sl,atecl his correct
locatjron 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 fronr
his 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,tcr
founta,in r,rhen he accj.dentalty brusherl againsb it. fn more extreme states
of 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 there
I 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 vorlcl
1s percervr:d. lnclis't inctty dur-i.ng thc ci.el-irium, an<l ccnsory input 1s subject
to bizarre nisconstructjons. Some of tirls may be attri.buLed, to actual
blurrjng 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 total
conte>:t of a visual or auclitory cvent causes subiec'bs to state t'ribhoul
fear of clisbelief that "there's a possum on the table" or "a big black
snake urd-er the becl-.

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(c ) occasronall;r rriggtous act j on r'. I r. be takcn to d-cal with th:le
pcrccit 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 lnagines
i: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;'thc
heels 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 of
hrm); but, -l-ater, parLicul.arly c1rLrlnlr ihc nigh,l,, they nr.ay bc.61:'LganLjc antl
terrlflring. fl1,-ll-l- l-a-t,cr,. i"n placc of cl.cuhants ancl giarrt snaile$, lrc iees
ra.ts, squirrcls, or spidcrs, ancl. graciually tJresc clin:-inlsh 1;o i:ecoine br.:-gs
or ants, t.'irich he -labors 1;o brush I'ron hj.s cloLhing a.r.rL bcrirj.-i-ng" Final-iy,
thcy iLisappear or arc corrcctly rcrccivecl as piece s of' l-int, clusi;, ic,ose
lhrca.ds, ra.i scrL marl.,ings on t,hc: f loor, na,rl hca.cls, r:ainb d_rippj ngs, ar
whatcver i'c is 't,hat lool<ecl a.nir:a'be a few lrrturs bcforr:"
(c) 0ne of thc t,l"rirrgs that sL-erts bo conl;::ji:ui;c "i:o the persistcncc
of 'bhe'se alinra.'ced, :llltisions "i s t;hq: rr-Ls;ual- lnrprcssi-on of sudclcn ra.picl movc-
ment of sma,ll a.mp1-.ltuc1e, r,rhich sr-rbjccts repc.rt rrhife ins';ectj.ng tire si;ots
a.nr1 spcclts thc;' perccivr: a.l irugs ancl a.ni;s. rt j- s ql'be pcrsiirlc t,hr ;
smal..l ri;rs-i;s161",1 d. tilov*Ilents 61' thc e)r<-,r; thcnse]ves, anal-ogitus to thc f16e
i!r-'neral j zccl 'hrernor scen dr-rrini,; 'L,hc rccovcri" pl'l,sc in mos I- suhJcct s, givc
ri.se to thc bcli ef that thc: e;no,us or spccl',s are r,rzrlti.rrg su"d.clcn darting or
fJrtting r',rovements and-.t,hcrefore mrrst bc j-nsccts of somc scr::t. I,,4rcn
askecl 1,o clescrjlte the a.ppa.ren't, rnovemcnt i.n grca.'ier cleLai [, one subjcc{,
reportc<j that the spcck u:rder scnrLjny molcil cvcr,)/ so of'Lcn anrl then
rctu.rned to j.-bs origi.nal posllion. The est,imatccl excursjon w&$ only arr
elghth 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.:rJ
mlsinterpretnl,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 tiroughts
from 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 rcsulting
e>'pe::iences might r^rel-J. be conparccl to the events d,uring slecp that are
cafl-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,.r
slrni-1-ar to 'cne prelcgica.] assocj.ative thjnliing Lhat occrrrs cluring normal
d-reaning; yet t,he r:oto:: equipncnt ths.t i s nor.nal-.ly inhibitecl l'rom "acting
out" cluring rlrcams has frec rei.6n to enact the irurer e>pcri,ence.

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CONFIDEN ;-IAL
(C) Attentlr-,rr and- ,

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

.J9"y-!rv-,i.1. vc.Ll cr-n il,s r'1ay, pc:rhaps rc-i;urning to norrna.-l iry tirc thi rd cla;r.
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:cl
b)' nanrc (r.riricit nny 'lrrod,uce a ste,r'tlc rcsp,,r""); :rrrd inai:i.Llty to ru:inta.j-n
vigilance in si'r,ur.rtions d,esiSTreci to tcsl this furrction.
(C) reuol,c cvcnLs is bcLtcr prescrverd. than I'or rccc:i1i,
-rr'{en:o-11'--!or
otltc!: organic b::ain s;rndroncs. O.ucstions conccrn-Lng
-o:93Jle-re-!fr-q!-}-lf
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;Ject
repcat, coruc,)ct-l-J,' r,ihat hc ha.s jLrsL, reacl from a, p/r.gc, D:iglt spa.n depcncls
on thc rapitiit;7 r.rith rrh-i.ch thcy are gi-vcn: if. givcn -i;oo slor.,..l-y, thc earfj.cr
ones are forg|1,1;en b;;1,hc tjnr-: thc l-ai;cr. ones are givcn, Rcca'Ll of digits
j-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 igjts.c.l

(.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 take
a 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:spondcrl
itlappropri-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 oll
retrieval 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 the
per.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: of
emergcnce frc-irn d.cl-jrium, but clerrcl.ops furl;ircr as timc goet by, nuch the
lray d.rcams rccr;'llcctccl in the morn1n6 ar.c f'orgotten by noon. I(any
subjccts dcrncnsi;rated that :l f' q.rrcstioncEL carl-y, nan.y of thc paraloici
mi 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;r
remcmberc-'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,r
the trnditiona.l mcclical- vic"r thnt o-ei,iriun i s charact,ers.r,crL by subseclucnt
a.mnel.i a.

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-
t '.
gether since 1,he;' 56etr pa.rallel disturbances. Ignor-lng contcnt, all
fhrce, 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, voice
develops a nonotonoLrs nasal sound-, a.ncl volume r,ralrcs to an almost lnau.cljblc
levcl . I'his pcrioil. of incohcrr,'nt nr-rtlbting is sone.l,imos rcf'erred to jn
old-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 ire
a' qualj i.;r rf i,lrcrc j,s vcry poo,r, recctnb] jng thc i.rorl< of' a. f'jvc-ycar-olcl
chilcl, but nrc:::e tilie an adult, .,rj,tit e:d;cnsj-ve brait: Clscasc. Attcmpts to
rJranr a, i'a.cc bi' onc highl). intc]-.I igr:nt srrbjec'l at l5 hor,L::r; procluccrl only
a sllc1;ch;r ';vc".L l.rith sone noniLr:scri1:1; m,arks; he r,ras ou.l tt: :lLrcapable of
drawj.ng an eniirc fi.gurc.

(c) rlhil orgilnizatlon ,:f r.rorrLs j-nto neani.ngful senlcnces; cotrtj.nucs

t<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 cnunclatc
lrorclr; '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 to
rnake comc scnse from a seemingly :incohc.rcrrt stal,cment.

{l:) r': ii-'15l1age

I'}tcs<: l-: . f rrl i1:r 1- 1;'1.",1"-' l-';:t::1- j-ons and- clistrlrl,jr'r:
elcnc"lbr arc- a-Lmost impossib-Lc to irruL';atc--thcy:;ccr bo rcsul,t from an
extrcne 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 arc
usuatly unsucccssf'u} . ft clocs nr: good- to say "htrat clo you mean by that?",

ilti$1"il'$$iFlEffi
 coNr ImH t'{HsI, I t LI D ;ru [$ffiffitffi$$sffi$
'because 'che sr-r1:;i llot l(-nov r+hat irrr rl d., cloc s n re&-L-Ly grasPit.
ec'1, rlocs
tire qucs't,ion, ancl niay uot rcalize l"ha'b hr saylirg vlrcn hc answers
I

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

but not
bY the third d'aY'
a "[hor-ightf'u1 or analyi,'i"ca1 one, is usrral]y attaj.necl 'becomes
l'"'i.tlng shol'Is progressi'vc rcturn to norma1 size, and reacling
'bime'
crcurate at slbout the sarnc

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

(c)hrhc.nsulljccted,;othe.inl'Iuencesola,nelfectived.oseofl3Z,
some in.Leresting ta,irc place in the rrolunteer's abi1lty io ap-
ot,In menr'a1- con6ition' Ai'
pi:a*Lse both t1e situaljon arou'cl irjm a.nd. his
"|,u,ng"*
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{e very often l-ikens
a rnay clescribe tlre feelilg b1; comla,rilg j b to a]'cohol , ancl of cke'y'" Obher
j.t to thc ei'I'ccis of "l.O-12 t,,r""J-,r" "aboLLL I shobsfeel r'rh'i
very dizzy-'
coltfiion dcsc'ip1,ions jnclucle such sta.temetrts
ets: "f
i't1''i:ocl-v f'cel-s like i.; veighs a ton'"
can,t seem to r.,";;"",y';;i;";;; or
or,,f can,t lie s'[i]] --rY legs keep r'llnt;ing to rnove'" fhcre is co'sid'erab]e
a good- cLlal- of apprehension asr;ociatecl with this
<11 scom.for-L ancl freque.L1y
phasc, r,rhich cinra&eris,cical-l y occurs between I ancl Iin my -]-ifer" or
hours af'ber
c?+)osurc. n".,*"fru fin* "I ha.rl nelrcr f'elt ljl<e this
,,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 '

inri'ivitiuals nicrcllr ::eport that t'hgv are rlot'iing

clol'm"
(c) $':me
at th-Ls point'
rr.hcn a$kerl irow rn"rr th.cy are.ablc t,r thj'nlr o" co'tc"nl;rate as "f
more prccisely'
but ot;Licrs arc al:lc'bo clescr-.tbc i;he r.Lit'ficul-ty S'bari; tO Say sOmething
Canr,t :lemenrltcr r.rha'U yOu jUs'i; saic1.r" Ot "l',thcn.I
jurnp eis3"' 'Ihis
I forgc.L r+hai I am say:i-ng--n1y nr-rndd-j-rection of ihcsomc-'fllcre
seerls t,o
strcss or thouffht is
pecuuar _l,osl; of,961111()l'bheover'uhe
1a';cr phases ur ti',e atil;j;-("1 atr-L] hours)
:rost conspicr-rous clurir':,1 -Lhan p i'r ir'r'nflllectccil'
tr ',.,
)\ ,, ,::r.'ir nrr'' l,i-.'1.a,.,". '' ,,':''l-'"' ;:rr. to be no mofc
.i
with only the nrost tenuous
seqllenc€i ol r-iRr.elatecl phrases a;:iql actions,
'bo 1'lie nc;rl"
comcc'c.ions f'rom one
phase into the
(C) As t,he cle1-lriurn progresscs through..the onset'
d-ccres'se in the number
phase of stttpo]a *;-t:e itottts,*l-'ltcre is a graciual cessatj'on t:f meatl-i'ngful
of reports t'r'crm lhe sul3ect cu1 njna11ng in a1'o1;al ftrc cnti::e sequence may bc:
vcrba]- oul;prrb 1'or a p'criocl o1' sc'rcral ht'rurs' lclst duc to
likencrl. to a nrdio bt:c;ac1ca.st t,hal a.L firsr, ir internr-i'ttcntly
i'ailln cclt'ry1-c.l;e1'y into
atmocp'r:r:Lc a.,rc1. tcrrajn intr:ri'cr.'(ln(:c: anl i'j-nilll-";t
silencc
(C)l',rhenrad'iosilence:is'1-iI-'i:eclrsotospea.ll'thebroaclcastsj'gnal
.',riil, tite otiset of total cleliriu:m,'
oncc e.gai.n bccorncs a,ucl1blc, b'r; r,,r,0,
secln 1,o bc a jumble ol signa}s
bhc mecgagcs naitc -].i.i,t}r: Or I]o sc,nsc.ancl

rfi$ [r:(

ffiANTEpliW trt h-Lt

* ==>
 'I

"
)' ,tJ
Ja-G'

coNm{i$fi,(l:[
.*

:r
!! -daa
[$ft$frt&$$shlffi
Y 'st ---
t2/vt
,\jo
'. '{ from sevcrai c1jffcrenL fr(lqu,:nciesTfl'Lir: kalejd'oscollic quai-ity of lhe
-,
-7- l;oxjc cLc]-LriUn is i.rhat nlCres it sr-lch & i'r"'c-t,a.cr-rlar
_' '-,1i '-,
d'i spla'y of rncntal dj's-
'| 'aJ (-t orgarization. un-hkc the schizophrenjc i sychosls, fanr-Lllar tc; the
consis'bency, no trend',
' '{i cli"nj-ci.an, dcl.-irjun at its he1ghi shorrs no then"ticsct of clclusional
]:]o obsessional- preoccllpatjOn r,ri'bh a sin6lc related
-."ic
-l
j-:rto a persecutory or gra,ndiosc systeln'
-i.r1eas, sys.lelr,ltical-],y conlec[ecl
Irrsn;eacl, there is a d.cgrec ol',looscning to the associai,ions that
-ti-i
ailpToaches
l'--.-

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

-..! :: references ald all,usions ctl,herrbimes a.ltcl- pla,ces, bricf' periccLs of
I I 't'r intense exe.nditetion c)f trivia,L bbjects, fa.cial
l
expresslons of' perp'lexitir
-(
,I(j Or l{ona|errneut, c|r-lckling amusenlent or tcncler concern, rcpctilJiou5
ti
.t fingcring or' bcd-Clothes or paiamas, su'clclen reques'l'c for inf'oruation or
't hai, arc prouptly forgo1tett, an;- so forlh. Irlhen
perional- artj.c-Les
Lclclressctl , the resllolirje is ofteir courileous and noncollrdtal , such
as
tC;"; 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 fcature
is 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"hofpartial-
the
success'
presence
Ttius, i'b is nct tutcl-)1'ltrl1on to wj,tne':ss sub;; ecis complain:i-ng
of'biLgs, snal1c$ ancl rodenls in their becls, or ins:is-bing tint"bhey j
them-
selve s ot: sono gcr:graphical-l y rl-istant membcr of hclr larn:-ly
"t 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
\v,/ d.sni.al. r-.f im:a.innent d.oes r"}o" seem to be a conscioirs effort
trrr-ru<
{Thi
io fool. tlte e.xandn€jr, Ilor to hitle the ernbaryassing llnor.rl-etlgC iha1; one same
.rln.-i.,111
'c nr\1 nakjll.:" ;r ''|'ery 8ood shol'rj-ng' f b seems rai;lter to be tlle
pntiC:'tl| ';irii':i"ing' {'f:Otn
ltlelioliicttlq -l.r:ng i'i;;','il 1,1) i)!i ciLi,,I'a<-l'bef:iSt'iC Of<J-isturtra'ncr:li.
. brail injur1e s or o-i,itcr organ.lc ner..rrol-crgical Such lnclivlcluals
seem imable tc appreci-ate ttrc reality of their d.eficit,s, and vill offer
j-'or their fail'ure
rid.icrr"-l.ous alib:is arrd- r,rikl-Ly inrplausible e;<plenations
to perlorrn a.t1cg-Lately ip thc 6reas aff'ectecl by their disease' St'all1ng
tltc
ancl tcnrporiz,.ing nulrleuvcl's, fllrch as asiti.ng thc eXeniner to rt:peat jn
quertJ.on, ot: B.skjng fclr ciarjf'j ca'b-i.on ol tltc :instn-ri'i'ion l'rhcn :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 vcry othcr
grosri cyror,i tr att assigllcd tasl.", they','ri.J.l comment, "f ncvcr was 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'Lhal agent,, tlicy r,rill emphati cal-Ly re,iect
this f'el.ce-s&ving nobjcrnand.in$j st they are quj-te capal:le but "cou-]<l
d-o jt trettcr oriifr a penci-l- ancl- paper" or "coulcl <1o 1b excep'L n1y
vlsion
1s a iittlc bl-urrryJ

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[$ffiffi1&1$$ffi[[u
#

(c) ft is paradoxi.cal 1;ira.t one of 1,lri,nrost rehlable indications ol

recoirery 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 has
6cii.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 usually
d.evelop a. Ioss of insight int-,o their cond.ition. lfhen their reactlons
''become slor.rcr aircl their errors iricrease, they recognize it and rerpori
r.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 thesc
tnllder 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,sonably
o'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 others
than 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 tireir

classic rnonogiapli "Delirium and- Al11 eiL Statesr" the ernbarrassmenL of
brajn 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 during
alcohofic i.ntoxfcation, the j-cl-josimcrasies of iniijviclual personallty
manif'esi therasel-ves. llone sul.rjects bc:come irritab-le, verba'll.y abusiver
or evcn lhJ'sical-l-y aggresslve. Olhers are quict, passive, and absorbed.
.in contemplation. Some are able to sleep through much of their disoriented
period, whi.le others seem cleterrnlned to takc an activc appr.oach to their
bewil.<lerment, explori.ng, tugging a.t walls, cloors ancl t'urnri.1,urc, clemanding
E::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, nake
joking oft'-co-lor renrarks, boast a.nd. sr.ragger in a grancliose nranner, and
lnsist 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 thc
co-l.cl eva.s-i rre vjgilauce oY' lire pa:ranoic lncllvidual r,iho r.eacls sinistcr
purpose 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 the
experj-meut as a challenge a.nc1 mai'le a cl.etenuinecl effort -t,o fight off the

-r'i j'
lEdtt$llttr#Blell.rk*.* ' ' 'J:d;mW'-

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c oN 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.l
jmpairnicnt 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 jn
thc 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 . It
has ol'ten sce'rnr:c1 that i"nrna'i:,ure or rcbcl.l ,i otrs'i,;y1-rcs arr: inclincd t'o tlrcsent
managentcnt problerns ahcl shol,' poor coirtrol of aggrecsivc jtrq:u.-Lscs cluring
the '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 by Lal1.,ing aboui, '{'rrg1g1g5" ancl "'u't:nccrC" a,nc] "ovcr'-
a'
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 prescltt
this clocs no'i: scem to be possib lc.

ffiW uitilLh$$iqx["m
 FG

corvFm'rAlllli:[,,i-[.tl: t!$$ffiH"fi$$* Iflil

T
rtr. (c) trvAruATroN oF rnItRn.ltiitr/,L DAT'",.

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

1. (c) r'n.91lo$ogg" fg{gI
11 ' fhe manipula,tion of numcrica1- val-ues obtaineit in thr: course of'
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'or
scrial 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 or
recr: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, it scemed 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,clue
tlrat rclies upon nxrre 'ultan onc :l nriica.'|,or.
a,. Dr,:-v":lollne;lt, oi_'bhg_.T$.

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

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, lotrcrrng
of i:erforra.rlce scores in su"ch t,ests as arithmetic al-.rl..J i,y, and cl.evation of
blood 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-ing
adrninlstrat,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, a
gccrrtn8 tab]-c lras dcvelopccJ. t,hat gjven a r&nl.j{l r-;f pci:ccnt sco::es aesociatccl
wi.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 scction
on Erqlerirnr:ntal P::o'Lcco-L -in Appcnciix A. ) ttrc scorjng table for performance
is shor'rn in Figure 12, Appendi.:< C.

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

EpilfFrqqlrffi Flilitl"it.$$iF!tffi
 " 'F
dc
lAl+ LU g,
#+iw ,!

"I25
0)

o
-'3roo

t.)
. L,l I>
d
k
50
.H
(J
+)
€ 25
g.l
14
t)
fJ
.'fl ,<

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.jectts
mean percenl; score r:n the tr.ro sabtcsts j.s refer.rccl to the tine pcr:_oci in
rsh.Lch it r,ra.s adrui-nisterccL ancl is ccnvcrtecl to a "sca]_e scorc." fhis
scale score i.s a trumbcr fron.L-9 a-rd. e;quals the close jn nr-i.crogram.s pcr
kilogram associabed r.rfth the subjec'c's percent score at the parLicrilar
timc ulder eonsideration. For example, a perfor.rr.ance ,score of 6O percent
at'l hours receives a scale score of ll, ind.lcating tira'; tr pf/tS is the
ci.ose mos;t likely to resu]-t in such a score at u hours. Tnb same scorc
o.t' 5o pr:rccnt aq 1.) hours, on thc o'i;her hancl, recejver; & scal-e seorc of
i, lreeause [1 itilf\ry 1-1';ir1.r'] lir: the close rnost likely to n::odr1,; .-1,r1ch a scol:e
ai, I.) hours. Atl per.ceni;age pilrforrance scores are converbecl Lo scale
scores 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 the
response curve [5-lo irours ]) .
(U) Slnr-il-ar families of curves have been d.eve-l oped for heart rate
and. blood pressure
(C) Secause nany of the earl-1er cases c1o not contaln heart ratc
or bl-ood p}'essure observations beyond. the first S hours, a mod-ification
of the proced"ure used. to d.eterrnine the perfomrrrce :',nd.ex vas ernployecl for

c_L
^1
 coNEEElrrTffi
JAFI TFI LIIIT
these obseryations. The
9trgo9

t1rne
vvjvr
userl in both cases
r,ras to - I, the response. llnis pcriod of
va mean
represc'rr
rimen.ba,l

tlme 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 heart raLes 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 would
be 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"*

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

(u) Tlie weights chosen in combirring the separate indices are

basetl on sta,ti sti cal anal-ysi s of the intercorrelation between each
of these measures and dosagc. fhese intercorrelations are shor,rn in
Table l-.
(u) TA.BLE -]

CORRELATIONS

Perf. lleart Systoli c Diastolic

Inclex Rate BP Dll
I ll TRI

Dose* .92\ .BB: .1ar ; 511+ .9+r

il:':':ill-ir: :] L:
, )rPl+ .r9B
BP**

Systol i c . !l+o ,t+62

BP**
f) nz
Heart .oal
Rate.lf*

NOTE: A-11 correlations are of the I'orm linear Y to ]inear X. A11 tlie
above 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 soluticn

of thc fRf forn:ula r,rou-Icl call for calc,rliiLion of the beta coeffi-clcn'o
associated 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-Lon
r: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'ficient
of deternr,inalion for' each variable:
(oose vs. Perf . Ino.ex)2 = (.92q2 = .B:4 = coefficient of
d,etenninati on

(oosevs.Heartltate)2 = (.BS:)2 = . (,J7

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

(Dosc vs. Diastolic BP)2 = (.rL\)z = .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 tlic
bl-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" TRI
sholm in Tabl-e ]. It shoulcl be pointeci out that the scoring tables
used- in d,eternr-ining the TRI r,rere cleveloped almost a year ago, and less
than tralf the cases cited" in thu. table of correlations vere used itr
constructing 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 is a. mcasure of'the d,egree to vhich 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" index
of jncapacltation:
. (C) Fordy-f ive sub jccbs who hacL recei.vecl
-1
closesof 1'1[ Irg/kg of' BZ by one of' four routes were sclected by the
investigator from the fil-es. 0n the bafLs of the total in,f'ortation

ffiffiffii;1"[$$tF!
 . .. ,. ,r r. r,'1 n ff fr\ l,
aaffie

coNFlffm-r iJAil t; I
'
t- L ]'-? U';,bJ.$tbbhd' ril
ts@dl*

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

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

Ittllci : 'to
l,lodera Le: i,)+
Severe: 7a

Follor'ring this, the obser-vations of behavior recordecl

in 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," nu:,lber
vere ind-iv-ld"rlally rctypcd. on inciex cards. Approxirnrtely IOO"n."
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.
to make inclependcnt estinates of lhc im cLc-rse they ruoul-clThey r"rr:re asked.
aslocjate with
the behavior ciescribed at thc tirne recorcLed", The estimates were avera4lecl
and 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, signiflcant
at the .OO1 levet.
2" (C) fne seconrf line of evid.ence was .ilre fincling
of a consis-L,cntly higli TIU (usually above 6.0) in cases characterizecl
by the presence of hal}_rcinations, cletusions and.f or vj.r:l_ent bchaviol
of'somc typc. (Sec I'able 7, Appcndrx C f'or tist of TRI anil other r"ooor"u
vafues in sr-r-bjcctc shorving psychotic behavior. ) hrhen probit anaiysis
. _ls perfr: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 ror
severe 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
is extremcty stecp (8.r J l.) aird 'r.t, J l.lr., respectivety),sorutions bhe TRI
' must be regarc1crl as predic'cive of'the
Irresence or 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.

e, (C ) Dcf'j n11,:r)ns ,)1, Cra.rl ,.-.1 c.rf , Sr:vcril,y

and Relatjonslllp to TRI.
(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.o
was selected- as a rninimum criterj on for incapaci'cation . If incapacitation
is to be consiclered a matber of clegree, the fol,loving four gracles oJ'

:*-:.-awftrylPFHFr{*
\,'^,r-rt l{ ' '.-. L. t-. tr ffi€\
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 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(rmc
tttr:ntal s,Lorrj.ng (lovest pcrf'orrrwrcc scores abor-LL
6O'f' at '[ hours), a:rd. no ]-oss o1' contact lrith
reality. Recovgry complete at abou'L )r3 irours"

l4odcrate = TRI of 5.O Su-bjects wjth TRI scorcs ireo.r I shor,' pcak heart
rates af 85-95, lor,'ee1; perf'onnance scoles of
abcrrrt 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 sevcrc
but st,ill l-ess than ma;:ima.L. Sedation xtay
bt-. 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.ent
conlirsi-on are eomrnr:n. Recovery conplete at
about '/2 hours.
Severe = TRI of 5.0 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 rcturn
above !O!1 untll ?-\.45 hours. Ile.llucinations,
conl'usion, h;rperactlve dj sorganizecl behavior,
jncohr:rent sreech, a,nd d,j-cturbanccr in rnemory
a,n<1 a,ttention charactr.:ri stical Ly appcs,r
follor,iing an early pcriocl. of d,eep slecp or
stupor. Rccovery complete a'L about !5 irouro.
l'l:,..:l:i nal - Tlftf cif 7,1., Henvf. ::ate ree.ches pealr rrn-'1.,r,,r; lf l,lO-1h0
r,rj.thin J h,lurs. Blooc1 pre ssuuc rise of from
20-60 nm I{g systolic. Raplcl onsc-t of stupor
r,rith.ln h hours, often prececlecl by pcrio<1 of
agit,alion. Pcrfornancc deterjorates to zero
r,rithin J-4
^t
hours. Stupor subsicles at 1O-l-5
hou::s, fiol-J owcd Lr;r pro i;r'acted pr:rlod of
s1-c.<:pJ-essne.ss, d i sorgani.zed ::andom beharriorr
cont-i.nual- lrall-ucinations, and sometimes
impul-si.re outbursts of I'ca,r' or Lnger based
on 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;*** irli$X65*!fi!
a. (c ) Re lati ve l:ti 'c1.--vcnccl b.y Varlou: RorrLcc.
(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
con_
ducted to date. Table 2 sumnerizee the studiei in hu.nans "ri_';ra;;;;;;ts
from laay t4t6o
to June r9q. The number of separate ex1>osures an<1 the d.ose ranges s.Luclicd-
r'Jere as follovs:

Docc li.rlge
Fgl]ts
fntravcnous 34 o.-l_10.0
Intramuscular l-1ir O.5-B;O
uua l h0 3.0_8.0
Inhalation o: - 1. lr- a5. r,l
Percutaneous ti: 1.9-60. o

30TAt, 2/r 0. r_bo. o

a. (c) Intravenous Routc.

(c) The effectiveness of thls route ls considcrecl
for eorrparison and is set at unity (r.o). As virlto ue
stanclarcl
be the
orrr
later in this report, the rDlox by thi",o*tu 1s'approximatery e-.)"ig1xg,
"t
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
djfferences from|he itrtravenous routc, ancl it is consiclered"sign1ficant
equal to
the latter in effectiveness
c. (C) Orat Route.
(C/ ll'he eff'ectiveness of BZ given as a sol-utlon in clistLlled water
on an empty stonuch appears to be about 0.9 ttrat of the iv or im
fhere seems to be a lag in onset tj.mc of atrout an hou:: and a slrnilar route.
d-elay
in at'cainment of pcalr ef'fects, althouglr the dose range stud,ied., the number
of cases, ancl thc lncornptete contj.nu:i iy of obser.-va'bions 1n 1;hls gropp of
early 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
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CONFIDEI!-Iitr
d. (C) i',1,,t_!.t,iortig5g.
Tablc I incl.lcates the nlr,uiber ''i' e>:posures carricd- out by
fonn thc agent, 1,he dosc rangc,
c+c1l mcthocl of d:.sr:erd'nation, thc o1'
I
and the particl-e size.

(c) TA]jLN 3

AEROSOL aposuRns ro Bz (u)

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

BAIJtr

Acetone solu'cion Aerosol gcner- o. B- 2.0 ro5-397

!t'
ator- -retention
apparatus*

Freon 11 susPension Acrogol gener- l-. t-it.0 z\-tt+

ator--ret cntion
apparatus

irlethy].ene chloride Aerosol genel:- rrl rtjo- 3)+I

solution ator--r,ran ex-
posure chanrber

Pyrotccturic mix EA thernal mu,- o.6 22-163

n:i tion--vind
1;unnel

firrotechnlc rdx Pine Bl-uff thermal (0.) Br-rr8

nnriri ti- on- - con irof l-ec1
respiration
IIYDNOCHICIRIDE

Aerosol. Scncr- 0.8 ira-: 89

3T IrJatcr colution
ator--rctentlon
o.pparatus

e retent:,on apparatus consists of' a ;IosEa syste.n o1 trilring throug

vhich the aerosol 1s Presented- to the sul1ject. AJ''bE:r each.
eicPosure,
thr,' amount of agent remaining ln the system ie measL'-real Ttre ci-l'fference
between thc amount presen-bed. anci the amount remaining in 'che sYstem is
the esti-materl retaitred d"ose.
 t,i ! i:,
' li ', .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. biratB'I]a.l'l':l'red- the sub;1cct
to acljust his rcgFira''cion b1'observing its effect oli 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 than
tu/,). ,

(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 sLuclics by the
thc usual
5O-TO perceni;. (ff.is csl,jmate r,ras clerivecl
f'rom ea:rlier
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 the n-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)'
jn
Tnc corrected
CT j; iot 1.rnrr,1al breathlng at tO J-iters per rn-Lnute a so-Ldier of
avcrase surcacc area (-1 .[3lr sq nc';tl::s).

(c) 'ly\Bln )t

CORITECTIID CT'S FOR SUBJEcts INITALIIIG tsZ llTTii A STAI{DAIJI Blulln!{ilq JA!."TIRI!-(U)

brr.al- Minute Surllact: A s grr-tn<:rl. rrcc'ccd

c CT Vo.-Lunc ll:i i5ht tr'lei1 t Arc-a Re t,en'bion CT TBI
Sub.r cc

rtq -1t't Or .UO

t)I 2,02/ 8O l_t-) [
Afv IJ -1
But 15,f)
-^
LI .Q
o
OO
Onn
i)z,v .)? 80 a6L li, :
--. o n t rl (10 ,'. ry
u.l
Iiod 109 -,_..1 ',J 75 Bg. o C. JU -L)tJ
"
t fr.,: ii i',
'l (:a
TI l.) (t,) bJ. J-)t
-LU9 -L
-r2 '(L ii0 t'',5
Sto 97
D 7\.3 _L . (X)
"r ()1
I t )\l
'1 rr5 '/ ()
m^h
,|l 0l rh.0 70 75.o 8o
Abcl 99
1O 1
5g 70. b
r,l .L/lft'z Bo 1)B \.')
t o.'z
Ken l-o8 rh. o 7O B:. tI r.)a
rnO
JO _Lrr I l_\ I I

.l

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

LJ
 SIRF(D{i! IAE D
'l,l*'t$$lilffi
the tLose-response rel-atj-onship was obr:i'i-',ecl ln the final- series o{'8
sdojects 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:arlly
as a pilot s'l;udy 'bo assess its I'casibitity and the ord"er of dosagc
requirecl 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 to
gradualJ-y increasing closes rn a vehicfc of'bcnzyl alcoirol," 1\ro of these
cascs, bol,h at bhe hjghest doscs tcstecl (lO-6O l$/lig)., itcvel-opcd scvcre
responscs, r,rh:Lch lrere cielayccl in onse'b ily al+-36 hottrs ancl thcrcaf'tcr
follovccl a course sir,ri-lar to tha'b seen wi-bh:i.v or jm closcs af'T-3 frC/tg.
a A meani.ngful- es'cinr"-be of relert:'Lve cft'ecbiveness by bhe percutzrneous
rou.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 of
iv equivalent d-ose. fielection of ceses lras goverrrecl by the following
crl i.cri a :
1. Itlo pre.riou.s e;?osures to BZ
2, I'[o trea.tment prior to5 hours af'ter exposurc (in
these 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 perralt
deterrn'iiratlon of the presence or absence of
hal"l-ucj nat:i ons, clcl"usionr:, ancl/or viol-cnt behavlor.
(c) For each case sclectecl., thc foll-owing data lrere corq)Ll-ed.:

1. Case number
2. il:se in nicragrams per kilognxl
3 . ' Route of adnrlnl stration
l+. 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

=:-"-CONFIDENTIAL
, ,I
Cii,:i i.^: r"ri . ','{qiFi$B
;l'iiyll"iuic'iiil Pu
-n
 B. Prcsence of ha'l ;r:j.natlons (0, lo, 2+)
c). Frescttcc of .rr,.ons (0, t'r-, a-r)
d-c-'-1

10. Violcnt behavic;:" (aggressivc, clcstruc'bivc, ol

a-^^r'ic.l-,-O'l+ L'I f'r-\
L'I
II. ;;;.",,UU--V,

(C) Co:rrclation cocffic-Lents lrcre computecl frorrr this cortpilation

ancl 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 in
Appenclix C and are summtrizccl in Tablc 5r folloiring pagc.

(C) If a singte d.efinition of incapacitation is 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'EZ
ln man is of necessity based- on 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 seem
reasonatrl-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 0thcr
Species on t]:e Basls of Spccles !/ej.ght.
(C) From cletez'rainabions LDIO in a vari-ety of' logpr species,
of the
en apparent relationship has been demonstrated. between the average
bod.yweight of the species and thc lethal close for that species'

cAt\r'ii-L[n::
?1
 ()
['rcsence ha.ll,,,:.ina-bions (0, -L+, 2+ )
of
C)
Prcscr-r.cc d.cl'r;r'ions (0, i-'r-, 2+)
of
l-0. Violcnt behavio:-' (aggressivc, rlcst:rrc-bivc, or
cscapist--0, 1r-, 2'r)
11. tru
!C) Corrclation cocfficicnts rrcre comlutecl, from this compilation
ancl 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) probit amal;rscs vcrc rurl f'or the totaf sample oi'tl5
Thr:sc
a' 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 the
presence of' severe hallucinat:-ons (H = 2) as thc response crlterion.
The results of these probits &re prcsented separa1,ely in d-etail in
Appcnclix C and. &re sumrurlzccl in Table 52 follotring page.

(C) 1f a singtc d-cfinition of incapacitation is to bc used., thcn

it 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 is of necessity bascd. on inclj.rcct evid.cnce. 0f'the nany c):-
man
trapolal,ions availablc, threc are recortrnended- here for considcratiotr.
They vere choscn in prefercnce tr:r rnany othcrs because, first, they seem
reasonabl-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:r
Species on the Basls of Speclcs Wr:i.gJrt.

(C) of the LD5O in a varjety of lorpr specics,

From cleterndnatlr-rns
B,t1 &pparent rclationship has been d-emonstratecl bctr,reen thc average
body veight of the species and thc: fethaf close for that species.

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

31
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\n-HP-5tr' H
-&=B
',-nc:\or\)t?P;H8\8N S
;-tr E\ ; q \' -r- *- 0r
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o
F)
=
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ts
p
o
o
(D

n)P 0\ \J] n) 'P c

\n lr-t I
--t ct\ N) +- P (' O Cf\ vn \n l-;
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! . L"r Gt. 'c. LL) a

[: r, il.i}'$i tr9f,ffi
=nConrinrNnar
 li i ,,,-li*;;;t'iilffi

fnis rel"ationship i-s alr inverse one--rlr:se decreasing with increasc iu

boclyvelght--and resui'fs in an LD)O cr;r,jnrgte -i'or man of about Z-'i ny/k1,
(e-) (c)@
}fal, Usjrng thc Dcri,cnstrat_eri li,ai,io
Ilstirna"bcd Lctiral trse ot' {crclpine in_
o{ k:r.hari'-y jn ArinaLc ilctr.rcctr
-;:-=----;-----:':--'-._ }t_e$._{!.lg_"".
,a ;", oi' scvera1. hundrecl hu:nan fataljties
ancl surwivals foll-ow:Lng large !:norm d-oses of atropine, a probit.a.ttalysls
lras perf'ormed" that yi"elclcd an LD5O of apprroximatcly lOLr p;/man. / Onty
reports.of'closcs above 30 nS were incluclecl, since closes uefow i,hj.s were
consid.ered. r.rnlikely to be of' suff icient necllcal interest to warrant
publication. (ft is recognizecL that bias in medical reporb:i.ng vou1d
s'bill- play a roJe ln the case of thcse hi6h doses, but the bias rnight
operate ei-bher r,ray: i.e., surulval of a high close rn-igh-|, bc a grcater
medical- curjoslty than cleath, r^rhile dcai;h I'ollor'ring a ctose o1'lcsgcr
nagnitude 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 publishecl
c&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 fact
wha'i, wss I'ouncl. ) fexti:ooks of' pharmacology give estin:ai;cs of' lethality
of LOO mg/rnan or !!ore for atrolrine, but this is a veq)r general- estinlate
arrd- is no'i; e4pressed in probabili"ty terms

(C) ft seems reasonable to s,cccpt lO0-)00 nig/nsn as an LD5O for

atropine since this is a broad sEngc aircl inclucles virr'cualJ-y alJ- the
assorted estirne,tes cur"rently knor.rrr. It l-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)@ jn
Ratisr of Phlrsiol-oglgj* Ef'tgctilreness Rg!:r.ecjr BZ sncl Atr%)inc, l.[an.

{c) 'JLr ,:r .,; i lrr,r,'-l :r i.j;,,.

.:.r r a varj-ant on (2) a].,r,,,.,.:, -lt has becn
shovn by Cu:rmlngs and Cralgb "uha'b the parasympa'bholytic ef'fects (hearb
rete ,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 ng
lntramu:;cul-ar dose of atropine in normal- .rol-unteers. Al-Lolring for
relatlve ef't'ectiveness of };7" b;y the oral route to bc O.l that of the
im 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) 5.2

rl5 =-

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

IIAL-
- a {ri#

--::cONffi'tD-IiN
.Gdq-dl@
[!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
a i'oybhc lcttral !6'i;ency ratio. The c:Crapolation of thc LDSO on th1s
basis thcn becotncs:
LD5O (a'cr,:;pine ) = 5 >: LD,O (BZ)
:l-00- 5OO ng/rran = 6 :i LDSO (BZ)
LDSa (Tfl) = 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: \t

{i
1. Species Wc16ht: LDJO - 2-, wWlke
H

a' 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 lirnits
cannot be assumccl in thls case.
c. (C) Es'cinatc o]l bhe LDJ,.
Thc clifflcuJ-"i:yin prcdicl;ing the LDI for BZ, arises in the
targe probable error fn the slope of a regression -Line rlrarrn tlrrough
any assumcd- LD5O. Dqqgps-c a,n IlD) is -tr:e {pr.tLre eS!-l!la-tio,t--oJ !1rc--,
i'rqJ:gg=:u,clog:J1[fi;"f tirc- LDjl-to neqcle:l np:o-)r- must be
"#. - ad.opteii as a "besr, estinrate.'t 1I1e sinplcst, and- "o*Jrigure
possjbJ-ythc mr:st
justifiab-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 to
i;r,r1,i; rr ,'r.Lc ol i:tr..r ':g::r tl:t,',JiLgir l;he LD5O. fhis l.lr:e r,i-; 1, -intcfsect
'l r;.1 .1.

the p = U6 l-rorizonta.L at betireen 0.4 and l.h mg/trg.

d.. (C) Sqn:r,?.ry of llstjirrates.
(c) In su:mery, consiclering al-l -1;hc j-nforrmtlon available, it
seems besb i,o ad.opb -bhc folJ.orr,i.ng estin:,atcs f'or the lcthality of W
tn n&n:
LDSO = O.')-3 rntlY.S
tDl = O.Z-.t .1, "f/US
III5O = 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
(l'baninef'uf s)
 "ii: ;r ',.-rnf
ilf$t
il
[ lLi;; i l3;$
-r,.i
",.);f

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

i-,. (c) il,-:": ilI;3glg!.
(c) To oc:tcr"nrlnc rtlict-ircr cultulaLive or tolcr"ancc- ci'fccl,s vou]d
appear as a rcsul"t of repca'i:ci- e:ryosure to J-ov tlosgi;, thc serj-es
indr-icated- in Tab-Le 6 rrerc carricrl out.

(c) 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 0.5 '( Fat:iguc, 65r:ncral- nilcl
trlr 7t1t day. iio
ma,l-crj r-;e
clef lnitc signs of ilZ eff ect "

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

cvidence of curnulative or
tolerance effect.
r.0 l,tlr:iural cffects daily, No
eviclence of ct;-tnu]-ative eff'ect.
One subjec'l, appeared to cle-
vel.op tolerance.
o/) I'iinirna.L ef'fcc'bs first d-ay.
I,lilcl to nndere.te effects
second. 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 nrbJccts

can be c;cposr:d. to as m,lch as O.'i 1rg/Iig of BZ claily r.rithorrL notlceabl-e
eff'cct on perl'onnance or plrtrrsi6-lsgical, l'unctj-on. Ibscs of 1.0 pg/kg
daily couse perceptibl-c efJ'cc1,s tha'b t,rould prr:bably not be.ol' pre.ctical
significance 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.g
d.ose group, the TRI scorcs roce progresslvely from a group mean of 2.8
on the {'irst clay do a mcan of ll.5 b)'the'bhircl clay. One individ-ual
e4pdlencecl. clcfinite ha.l-lucinations ancl cllsorien'l,ation beginning 6-tO hours
after the thlrd d.ose, )

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

:", :" ]:.CONFIDENTIAL. :

35
 e .t A ,r r,"l i ;l 1-) db

rlAl= Uto;U#lou lFlflts

r'!^t G'#
#.'\A!'i11fi
*{oNFIDEN
#
(c) lJ.rc meerl scrlal- perfor-.manc(r iroores (ave:'agc pcrccnt of' bascline
on nu:nerical- facility and speed of cl(iii,'.1'e subtests of' -blre Texas l3a'rtery)
are siror.m gpaphicaj--L), iu Figures 2 a:rd l, for the f.O ancl 2. o lqf\'.{f .',;ay
groups.. (Tire upr.rarcl 'brencl in tbc perf'oruance scoreri of 'uhc -L.O
group is attributabl-e 1:o practice effect. )
/ .\
.

(ir. (C) Effcc'i; of a

zu: Irruerwal. \- ) -..,
l]eco-ncl li;?osu.re Af+;er
"

(C) _1!g rure.lpcc'[ec1 o'bservation in subjects given a rcpea-t closc of

BZ 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 subjecbs

r.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 injection
'a' of 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 seven
subiec'bs shovecl a rlrop in perfclrure,nce scores that exceed-ec]. thc e:rpecbed
magnitud"e (baseci on t;he TRI scorjng tabJ.c norrns for this tl,ose) iry o
conslclerable uargin during the fjrst 6-10 hours. After fO-1,5 hours,
hovever, the same subjects shorred acceJ-cratecl rccovery, attainlng scores
in pe::form.rnce tlrat lrcre higher by a substantial n"argin (t-O-40 percentagc
points) ttran the expecteC values, Ai'ter !B hours, scores in perfonnnnce
corild 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,rn
graphically :'-n Figurc-' l+, superinrposecl on the curve of "erpectecl scores"
for thls c1ose. (lir:ar-t zate values shovecL sim:llar al-teratjons :flram the
expectecl time coursc. )

{Cl) A-l lrli'.;")r i'li,:r:"| ;i ;r r.3 n^efl explanation fcr tli' , ",,(,oolld-clo!c"
'l.

eff ect, i t s corrsi sl,ent appear.a,nce ln this group a^nd serveral- othcr
indlvldual ins-bances j-eaves no cloubt that lt is er definite phenomenon.
5, (C) Temporlr,L Responsc* Ctraractell st j.c.s.

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

^/'
iD
,t,
129

105

9o

T5

5o'

i+:.
l'

30.

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

r05 I

90

7L'
l)

6o \/
)+5. '\ I
3o
Day 1 ln.v2
V
hv3 Day4 I

15 I

o.
FTGURE 3
SIRTAI MEAN PERFOR}'{ANCEEOms FOR I+ SU}.}ECTS CI\ruTf I r.;,1

.,i 'l.i i,
-- CONFIDENTIAL ,:
:::
a'/
JI
 ,ryriflLft$$t$ffin

(,?
()
F{
o
CJ
[o
'rR
IOO
CJ
(0
a
olJ
T5
tr
h
(.) 5o
+J
.P
A
!) 25
),1
c)
H
0
II{)

Hours elapsdd- fron time of exposure (1og seale)

FIfiJRE

CO1VIPARISON OF N(PECTED W]TII ACIIIAI, SARIAL I'{JIAN PEI1FONMTWCE SCORE TOR

7 ${jBJECTS Fnrm-f riil -- IUf -"- -
Iurr,Osui",. $ii0idii\tu-"21\rD-mFfl"mmT

"Q
 :*. "- +,, CONFIEE11i
l-. Onset Time: [he tlnc at r,']rich performance scores first
clrop belora J! percent .cf baseliiie.
2. Peak Time: Thc 'uime at r,rhich per.for"rnancc scores reach
their l-orres'c pofff@ perfortnance clrops to zero and. rensins thcre for
a number of hours, thls
point is taken to be the nlcl-pojnt of the periorl
r:f zero perf'or:lance on a logarithnrlc tinre scale.)
3. Partial Recoverlr Time: fhe time at irhich performance first
cliubs above 75 perccnt of baseline d-uring the recovery period-,
l+. W: Thetlne at vhlch per:i'ormance clinfts
above 100 perceffiing the recovery perioct.
(c) Figure I incllcates thc tcqporal refercnce points for each UI
the four d.egrees of response severlty as intersectlon points betueen the
a serlal- per:forrnamce cw'ues and the criterla l-evels dcfined above.

Hours
\
-*-t'

(.)
7{
..o d

a 5o
0) fueY toe
t{ Recoveay
ilt, 7i me5
-'t(
gl
o
g
L
.o
I
CJ
O{
Peor
Trne5

rl_ffiJnx 5

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

[.CONFIDENTIAL
39
 (c)
results:
Tabl c Tffi r-rn Figure ), sunrnfi,rizes tl:e

(u) 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)

Itild. (TRf = )+)

I+_ j &ro 20-25 ,o-50
Ci 11 2r-35 70-Bo
lrroderate (TRI -q 2.5-3.5 (}I-L

lEAE L. Q rr 35-\' 9O-l-OO

a' Severe ('-L'BI =5) L. )- /t

L-2 B-ra )u-ou 100-til0

lvbxller (1BI =l

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

a. (c) TltA.

(c)
reve
iil t,roni
inst BZ in
Table 7 sunmnrizes the experl-ence r"rtth THA.

(c) ( ,* procluces a l-or,iei:ing of heart rate vhen -bach)'cardia isj

present, )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
u c/)
P. P.
O
P
I @
p.@ O Cc) o
PP
(D(D
a' p,
!>O
Ou) H P.
d
u(D
(D
o o
o
(,N

o
H

i4
P
td

14

r4
a o\ t\J
o\
oI o
o
rd
Ed
o* \c (,I

at< H
H
Et
* O
** r)

H IH
G9O F3 H
rxoo cl- P. IH
\n EEf
_+- qcDe
oFJ
F
o F]
J lH
HH ir" l--.1
{9oFl)l-4nr5
(.J
at, F o F'
t- ts
!
PJoi .f -c- 6e
cl-
H
cr)
o a
m pjo>

Fi
ts. oo
FIB
>
c)
p o
FIP
H
ra
€
C)
hcl

F'F
mAt
E.HF
Fry
SgSg'FF
Op.OcFtsO
FJ
3EF
t"5p.
d
N
Ct! FJCI'f ts'H
F cl!(r) Ptr F
P.P le rD crry Oct-0)
3 ci" N H) tr, O O cf O FhC {rD r0 cr
0q P. 5 o 5EFJ f-,0 u H.
o FIO cl- O O o
p,<ry(nt-bcf tr Pr\ o
uJ otJo
I cf C u rD O O O t.,. (tl-,t.. fr
+-o H o d c/B p Fl o < Pt(nf'JE
o
El co { O
. O p, << tO Ht U)
SriJ cf 4 O 0rl d'Fj
OO O,O 0r cl-(D ts't ry H'O
g, tr ts
C H h dt,.ry tdFJ t < cl"
ry 01 o',O OE N (n r0 ocq Og 0,)

. qry'
nr < ct tr fD < F cFo d
rD cr F cl- P Ho
h tsl I
ry rD p. NS4mFFb(nctsaD lrJcr
o Hg rcn E o { { X
d
tr,
b'6 :y tr.x
\J "J l-JP.i'11
o ru5{ IJO P.
u
o a
o<d O Poo(D
t oPF Ptrci-
\JFrFr
|J.oFFjIFjmOP.
O r a e 0o fDw 5
5 . .!-'- rl
!\ ll
il
fu4fi?urliiuro'
 I
:).
F
CONFIDEI{ ftAL
.*
q b. (c) I 'rinc (pir.ysosticilLinc).
$t @.*4!

t,
(c) De,.cauc;e j- i, hacl been uscd- succl,;il9lUl-ly in pqEenlg
F clini-
Fry-:-
call; ced
,'* in aninal *1r,ll;h-.
*}L4-..-
.)
$\} (c)
tnthe
Through trial ancl e:rror, optimal oral- d'osage lras found to be
neighborhJoa of L+,mgfnr, Uul, tiric value may vary cluring tne c1u131
q.
."1
s: , *uru" s a.!,s.f- -.r.eru"F.€L"m'can-"b.e.3chi*ev-ed-ui-ihin**
In the
be-nain,t-p,r"::-e-d*Li:ereafb-er'
H
J
e.n-il=ea&.
GT-E"Uiect treated", oral escrine r,ras given eve{X 40 mlnutes for J2 hours'
sq\ ;;i;id lro m:inutes after the injection of f yu/ue of BZ' A tot'af of
fs 2lo mg of eserine \^'as given. Tlte subject ilid. not see:m to rcspond to
r;'qt tren,tment foy the firsie,s he
5 hours, }:ul, a,t T houro drarna,tie improvement
emerged from a stuporous state in which per-
t sucidenl.y vas eviclent
{)rTnance was zero to score fO percent on the Texas Battery and shoztly
r{ therepr-f'ter to score pO percent. Appetite, sleep, rnood and activity
Kr, vere 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
follor,rin6! exposure. In each case, using oral closes of from 3-\ ^ t.
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)
-r,.)i.- l;ii;it-i-tr
.,J (7r.".-rr Jl lt, ,.: t';; il.rt,l lrl-l .lr.r"Cina.tionS . --5*,."'
';--..^' ' TilAr
ine doe6 n,:t se*n to matcr.i alJy $horben the overaLl duration-,of. the. "gg1-1.1"1'r){l

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
. TIIA nn.v- hAYc"!o&lc plopeI-tie"s,.not."shl::a'1,J"# *
?frog*-.- Neither .1s ld-eal. li'ry
w*-:*'"=
636-rr"o np6 11uqJ !S -,Ki.v-gn-i
! *r -.^ r r .- J+ *n
. JjJ.ird"esLl&--I!=99,9mI
^1 ^^^--

ffi J,.t o ." ot o'"€,t;Lue--f

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

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
f
a\
I . .:.
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 with BZ, eserine vas e:tnployed in a d"ouble blind' pilot
I vo]untcers e:<posecl to 'l yc/kg ct' BZ irn'
"t"Jy-iiith -bo be
(C) fhrouglr tr1al- a.nci. r:rror, optimal,oral- dosage vas found
in the ne:i.ghborhood, of \ ngfnr, but this value nay varyobserwation duling the course
of treatmcnt f'rom e-6 Wlnr. bV caref'ui and- contjnua] 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 thereaf'ter'can be achieved lrithin
8 hours of BZ administration and. can be maintainecl l+O In the
tast subject treateci, oral cserl.ne r,ras given every 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 not seem'Lojmprovement lcsponrl to
treatment for the firsi 6 hours, but at J hours clrarnn,tie
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 activlty
were 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 in
t::r,:tlr L,tij.r ,ll Iiltl'f '.; ::lt,l ]t!l,.l t-r"Cinations recurl'err, 111 " iir'r TIIA:
t13., 1,rj
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 to
be 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

CONFIDENTIAL
Ln +a
t
 rfll,lf
,, l-i I I ll
".-#

#oxEiDrN{4g:
--
!Jirwr

lndividualseems less energetic, less in food. or recreationt

jn!,ereste<l
and somevhat cluller mentally even thou;1h orlentcd and cooperative' These
observations corresponcl to those of ot;iicr investigato::s vho have observed-
of lntoxicatecl cats'
the effects of both comPormds on the behavior BZ
PooslblY some difference 1n
nervous syst
fn cf:-nical features with the tvo c

!t'

sfI{{+ffi
t+:
 -..: :CONFJDEN }. IAL* :ri'iqkffi$l
,J',,tlui 1"'
l' \i\r
!IrJr.l\ll.

n. (c ) :Is,Lq.rlgg otlglilg].jlgrfgrytats'
(C) fire effect of the ac';ual- skil-Is reqirlred 1n cornbat is
RZ 6n
iargety air une>qrJ.ored- sutrJecb. What tittle infornation has been obtained,
al-bhough it cannoi be caliecL rigorous from thc s-bandpoint of experimental
design, 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 ofinBZ by thg lm rou"be'
Four mt:n receiving the lover close sholrccl zur increAse the nurnber of
eryort:; arrcl -i-n -Lhe total- assembly tirne that paralleled- the iupairment
a obscrwecl 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 until
LrB-]Q hours.

(C) Rlf'le aim:ing and firing, sirm.rl"a'bed. with an electronic rlfle

and 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 of
light on the wa}l near the floor. fhen, putting his r:fle clor"rn,lrrelevant he begatr
nui:"f :r opeling some carrlboarC cra-ues s'canding nearby r-urtil this
activlty 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-lnch chameter 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, practice
rras 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
tlre onl.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;l
ar'ol)' [rre otn'er indi;idutdfifpibgitiftfrf-u clegree of lncapacitatfop"
,l
4+
 ^' ' i "i;:iiijq
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';t)t'A
E

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

(C) The effect oll BZ on the aci;t-ial- skltls rcqulred in conbat is
Iargely 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' experimentaf
deslgn, appears nevcrbheless to be useful ancl vorbh presentlng.

t. (c) 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 a rehearsecl
to a -levcl of' proficiency accep'bable by infantry stasd"a'rds ln 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 iqpairrnetrt
a obserwecl- 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 rlfle
and 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 of
light on tire wa}l near the floor. fhen, putting his rrfle d-olrn,irrelevant
he began
tui:"t1, opening some cardboard cretes si;anding nearby until this
acfivlty \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\-inch cliameter 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, practice
r^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-y one 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
ine otti'er indlvld.ual
_,. d.egree of lncapacitatlon'
"f"o'.)' -g-hlrred Ufre'- ...;p.dpictl
CONFIDENTIAL
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 with
his base"l-ing-i;'i nc ot'one udnui;c an<1 t,cir ;econds, anrl recluired- closc
ettencla: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 timc
of less than l0 seco;rtls.
(C) ile threrr f ive grenad.es v-itlr poor accurac;r (al"cer clropping
several of them) ancl only wj.th contj-nuous coachlng. IIe r.ras'.utablc to
assist effec'LiveJ-y in erect"j.ng 'circ pup ien-b. Ile succecdcd in dclivering
a 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 to perform

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 stuporous
and" mumbl-i"ng incoirerentl-y. At this 't:ime he rras also lurtestabl-e on the
Te: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 breabh
at the slgnal anc1, instead., took a d.eep brcath. IIe uas of no assistance
to his partner durlng tent asscmbly and, in fact, pulJ-ed up several
ten'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 continuous
instnr.ction and encouragemcnt by his parlner r.rho by nor,r lras performing
quite ru.el.l . D,rring tlre message carryi.ng, he caluterl srnartly arrd ran
half the d.istance, thcn sud.CLenl.y mad,e a pO d-cgree turn and" l,rotted. off
inbo the r+oocis, lle uas flnatly intercepted and brought bacl'" after he
had nrn al^most a hr.rnclrecl yards. Ile fatcr explained he tirought he vas
rr.mnj"ng the obstacle course ('cyp:lcal o-r bhc "alibi bchavj.or" seen at
this stage). Grenad-e i,:ssing a:rd. the obstacl.e cource werl': qucecssfu!-I;r
-*-,,.,ili-1'lr.l''r:ii,1r, rrrn,r'i),ioI'Li-Ld time was prr:1olr5e.L ilrl,rL-rrrrj bascline.
,.., lrr,,
:',.r- ..rl"-r'-,1
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 mcssage
on the message carrying -back, even though he rnaintaj.ned. an appcaro,ncc
of cerlalnty and executed cr:mnands strtarLi-..l , Recovcry r,ras complcte
by the fi.fth day.
2. (C ) G:'r.,r:.I Pcrf'onralcc.
(c) 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 vere
fanri.l-larizerl r.rith el-ementary ffeld proceclures, incluclingthc operatlon
of a flel-d telcphone switehboard, a \,"alhie-tallie, the recorcllng of

lPr 'q nn t''

CONFIDENTIAL
)+,
 UtttLft$$IFl[$
messa,ges and nraintenancc of a log boc,l.,r :nalntenance of a cornba'l; situatlon
map, 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 tvo bunk'sr Lister
bag ancl fie-LcL rations, table, chalrs, wal1 map, f'icld telephone an<t
I
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 for
rnotj.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 of
the 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 task
i^ras to ansvrer ancl initiate ca-Lls by one or both uethod.s of corrnuricatlon
pncvld-ed a:rd to c&rry ou-b incorrlng instmctlons, reeorcl inforrnai;ion per-
'caini.ng to nrlll bary ntovements, weather, intelligence, etc., on the
sitlratlon nlap a.nd- 1n the 1og. At predesignated. times, an offl"cer entered.
the enclosure to tlake a brlef inspection. No other contact with the
outsid.e lras permlbted, except by means of radi.o or telephone, tirroughout
the 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 to
other 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 with
the effects.
(c) Within t{o hours Z (8.0 im)'rras too clrr:wsy ancl ataxic to
continue 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 put
hj.s nesk on. For thc next tvc.r days he r^ras disoriented and" hyperaetlve,
becoming lrritable ancl lncreasingly detenuinecl to leave the enclosure
on the oecond. cia;r.
(C) H (5 im) arrcl C (5 acrosol) wcre affectetl" to lesser clegrccs,
ancl wereable to 1:erforrn vhat ms requ-ired. of thcm reasonabl-y trcll- by
the sccond day. Irh:ch of thcr custoqlial care of Z fell to L, hotrever,
 - ,. F!t 4_l
''rt r"'il'ii { t

'r;i i
i rr . ,t; I ,i+Jii :lull+t
;COUEID-EI,I f IAL""- .:
-- ---

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 cgIl
rrj.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- rcmsrli
like "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]re other srrbjec-i;s, larLicularly L ancl II, s]-towecl renuarl<nble
a'
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 casual
vigilance (".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 wtclerstancl
r^ihy he was being trcatcd as thorrgh he r,rere helpless.

(c) On the second day, cod.ecl messages were racl{occi. to the men 1n
an effort to provicle more challenging problems. Although Ii and c
r,rere both col-lege eclucated. a.nc1 of high intelllgence, they seemed, unj.n'berestecl
in decocling the messages. 0n the thircl d-ay, however, I{ rcsumecl trorltlng
on 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 that
although 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 his
full intel-1ect,r-ral- powers ancl nonnal i"nquisitive drive, since he gave up
quickJ-y on the code s.n'1 yet sol.ved. it read:iLy whcn he re]'rr.necl to it the
1.. 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, an
adrl:-ltiona.l- burdcn. They felt hjs he.LpJ-essncss would havc been &n cvcn
grcater 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 regalned
his senses was suggested, lI objccl;ed to'l"he';rcatmen'l, as lnhuna:re and
llkeJ-y to I'rorsen Zts conclitlon, but Z ir-lnsclf thought lt a vcry good idea
ancl. believed Lre vould. not lla.ve rn-incl.ed- restraint since he ctld. not know
r,rhat w..l.s happening anyl,ray ancl probably r,rould not have remembered. vcry
much of it later.

;rcoNFI+?ENrlAL
 .rLl-Y
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-"''-*":.-

(C) fhe subjects also

:":.T]#;l*5
iiliii]fli-dlie group harl been &ble 'co
cun"binue to fulflll- their assignments, 'trlcy had m'c1e a number oi'
raistakes
have r';erj-ously hinderecl
-i.n the recorcling of messages, et,c., tha'u trould
Lheir useftr-lncxs in an autirentic combat situatlon. A1so, if two o1' a
them
unit
harl received" Z's d"ose, 'bhey wou1cl lrave becn virLualty d"isabled' as
trnl-ess meilical coufcl lr"avc been accomplished carly and they
rel-ievecl of the responsibility of caring for the incapaci-
could. hanre treen",ra",,ai1utr
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 sufflcient
cllverslty a1d. challenge to a group of intelligent subjects over &n of
erbentlecl periocl of tinre. If a test is to provid.e val-id- pred-ictions
nrili'bary perfo:::nnnce, it is imporlant that the stimulus input be of at
sufflcieni coruplexity as to "overloacl" the capaeity of the subjects
cerbain times. E{rjally important, the situatlon s}rould not be ov€r-
a' simpli::'iec1 tc the poini vhere al] need"s are clearly provicled- for, Ieaving
no 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 is
required. 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-spacertt
he 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" , )
'Irl J r , I I I i I r

C-O-J"f"lDgP r-141," r- '

"
l: ;il -r-J.i

rv. (c) },gLI'IAICT [mDI cAL co_tlqIlERA!":|9JE .

A. (C) EtfegLivciress zurci iiui'ety'

11e estimstcs o1 effectivencss of BZ are basecl orl

experirlcnts
(C) sui:crvision' in
r,rith young rnales ln perfect heal-th, uncler close.mcdlcal f'ree of'physical
&n envirorment tha-b is clinatically itteal ancl virtually
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'
close wilI
locatiorr of tor.get personnel , mctcorological- factors, ancl),ho'
ct'c'
rapidly
Also clepcnd on vtre'Uirer protective maslrs are ava'ila1le,
arrd'propcrty.bireyareusecl.Anat,tackagalnstasJ.eepingpopu}ation
-bite tilie of e;<posure becaus;e of il-re acld-i bional time requlred-
arout.cl lengthen iu
,-bo rrrsk. Mj-nute r-olumc r,roul-d- be rnr-tch grea'ber in persons etrgaged
jnd:lviclr-rals rnight succcecl j"n holcling
phys:'Lcal activ:i-ty. unprotcctcil
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
.rolume, snal.I .inclividue.ls r'rould- receive larger
in deternr-lning rninute the of an inl'ant
doees ter, ki.J-ograrn than large individ.uals. In
case
res'bing conclitions
welgir.ing 10 pounds, the re'baincd. closc per kilo$ran
r'rnder
'L:imes es great as in an e'clult cxposed to
r,rotil.r-]- be appro:limately three
the sane CT.
;. (c) varraticql tt-',n f,'^.,n"r*i\'if
:11 f,/U!rUe l/ vr-
ilrl
''-! -J \'. .

(C) It has been rej-terated- often in rter1ical rrritings toxic

on atropi'ne
in t rnr"rrts and. ctr-il-d.ren are less able to r'rithstancl doses'
hnve survj'ved'
Tlris, hol.rever, ls cl.rr:l:. io guestion since small chilclren tltr'' ,l ";:c that
ilr..,l;,;; 'i;iiilt o* u i*,..i.l1r1 l:iiIrs' :j':]-c cq'*al to or highcr
oftcn are lethal in aclults. womcn-ao not secm to be essentially cuf'ferent
erperiruental evidence con-
ln thelr response to atropine than men. I{o -bhe
ceming the effective d-ose of'3:', in rn'omen is avail.able' -lrell.
Probab1y
agea ano clebll.Itate<l woul-cl toler:ate thc agent -l.css

(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-ancl t14:es, hlpertension,
rcrraL or hepat5-c cliiease, hypeytiry5oiclism, d-iabetee, acute or chronic
f"jf"tio"o lj-u"r.r*s of ai.l t11:co, partlcular]y respiratory illnesses'

i
"1
1. .ii i li
l,; \i i:
[ggNFIDENTIAL li' I
I
i: :t
.1
L

h9
 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,osage
b. Sublcthal d.osage plus:
l-. Unfavorable climate
2. Increased. rned_ical susceptlbllity
3. 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 respiratory
b. Dehyd_ration and. starvation
c. fngestlon of poisonous substanccs
d.. Accldents of'all- types
e r Horni cldal- rnania
f, 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.

(c) It lrould. seem pr.obab].e from a review of the above that if
ef,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 tethaitty
rnay be an lnf'requent occurrence, it is not d-ifficul-t to suppose that
j-n eorrblnation I'rJ.th th,:: r:rxtributory factors }1sted. aborr^, r :ignificant
il'acbiou of the potrujabion nrl6qht suffer fatalltiee; ch.rring the first
few 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) rnmed.late exploitatlon, prompt capture and mecljcal treatment
of caeualtles and contror of f'1re and otherpotentla].J.y catastroplc
oecurences nay nake 1t poseible to cleliver effecbive d.oses r,rith mjnlmum
Loss of l1fe.

' '-- 11"\ ;1 1' I lrr J"_ I I

-l

CONFIDENTIAL
5o
 CONI.IDEN I IAL

B. (C) Managcmen'b of Casua].,

(C) The fol-lor,ring prlnciples are rccortrnended in the rrarurgement of

m.a-ss BZ casualties:

l-. trlapic1 -uri&ge in the following orrler:

a. Hemorrhage ancl other surgical emergencies
b. Coma
c" Stupor
cl. Ataxia
e. Ambulatory
2. On the basls of' present knov-Ledgc, physostigm-lne
to be thc ch'ugs o{'c}roice. }lowevcr, know}edge is
and TIIA r,rould appeer
t
insufficient as to the inhcrent toxicity of these' compounds, and. thus
a far the close requlred has been one far jn excess of that encountered
in hospital practlce. Iong acting prepara'cions of these drugs would. be
nrosi d.eslrabl-e.

3. Comatose, stuporous, and ataxic patients

should be treated. in the same !:anner if cliagnosis is d.efinite ancl med.ica]
facilities permlt. Othenrise, confine stuporous ancl ataxic patients
in fliall groups or lnc1ivtd.ually, ancl manage conservatively. ff numoer
of patients is too Ia.rge, nass confinement in safe, cool area is most
important single measure. If lndiviclual- attention is in*oossible,
Judiclous rise of' meprcbamate or some of the phenothiazines vould" appear
to be inclicated since the prinary concern woul-d be to recluce the activity
of 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. fhe
feaslbth"ty of such 'bherapy would- require testj-ng.
l+, lnbulatory patients shoulcl be obsenr:d- for B hours
arrd. 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 for
flrst 12 hours unless clehyclration 1s a problem.

CONFIDENTIAL
cl
 IJTERATURN CITED

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 variableJ.Effect
, of Atropine sulfate on tr'asting Gastric secretion 1n l4an. 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, E. G. anri. F. N. Craig. CRDLR (in pub1icatlon). Physio-
Cunmi.ngs,
logical Action of BZ on Men Subjected to High Terrperatures and"
Ekercise.

e 6Nfi'D'Ex?lal-*-- tdffifit"R-${FEflffi
qt
 5
( l?
l

CONFIDEN"I-'IAL

*:
BH.ffirusts
{'A t"i u t L t" r
*#*dfrM6!!iff"*]a=5:::'
tl :r:: W$$fi!.&$$!tr18il

APPENDIX A

DESICN AND METHODOLMY

- [}NffitF{$$$ff$fiffi '
ffcrnnrgiph-trrrnl
w@d-'**'l+--:.l- -.. -."
 CONFIDEM'IAT
cA t\ u it l-fu ::::: njfl$frtft$$[FflE0
A.

(C)
(c) Genera

T'he
L

-
protocol that has been used with minor variatlons for
ihu purt l") months ts illustrated by the complete caee report that
appears et the end of this Appendix. Conpletlon of each case record ls
a iengthy process that begins with the inittal selection of the volunteer.
Fol.lowlng h{s assignment to the Program he undergoes very extenslva
medlcal" 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 consldered
for expoaure to BZ or other psychochemicals.
(C) If selecred to be a BZ subJect (only 20fi pass all phases of
this 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 to
establleh 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 of
these is an arlthmetic speecl test, while the second requires rapid
recognltlon and circting of four-Letter words placed wlthln a contLnuous
of letters (see sample form ln Case Reco::d at the end of this
""q.r".r""
Append tx)
(u) During the control. perlod, the subJect aleo is asked to rnske
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 in
rr i:tr,'.trcled eul"r:!"e te ) "
(U) the mornlng of the test, a llght carbohydrate breakfast ls
On
permltted, and fLutds are kept to a minlmum (to decrease the likel-lhood
of vomttlng and reduce the productlon of urine ln case of temporary
bladder retentlon). The agent ig usually glven at OpOO or 1000. lltare-
after he is observed continuously by nur$es and technlcians and at
frequent 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).

Appendix A
;.- -gaNgpENIAL , .;

il]F$ffi.e$$HF frffi
 CONFIDEN fl {AL;r il i, -- i ;

No. of Tlme .Periods Beg,ltts Ends D,$e!!gg

hrs.

I
"l
OO:OO Oa:59 I

E. O1: OO O1:59 I
t 02:OO o2259 t
l+ O):OO a1;59 I
5 0l+: Oo ojz59 2
6 06:OO a7259 2
7 OB:OO o9t19 2
B lO: OO L'l+:59 5
9 l5:oO r9259 5
10 20: OO zl+z 59 5
11 2J:OA 29r59 5
t2 10: OO )\259 ,
Lt 15:ao 19:59 5
rl+ \o:oo U+:59 5
t, h5:oo l+9r59 ,
L5 5O:OO 5\t59 5
tr
17 55:oo 59259
1B 5o:oo 6+t59 5
L9 55too 69rrg 5
20 70:00 79:59 l0
2L Bo:oo B9r 19 lo
22 90:OO 99259 10
25 lOO:OO Lo9:59 10
2\ l10 : OO LL9z59 10

(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 times
" f,*rnnerature, pupll Slae and rep,ctl i'"'i fiy to Iight:
r,"ach); res1, 1ilTTr,,rl,l
(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.)
J" tsehavior Check-Llst: (A ratlng'scale designed to record
presence of principle signs of BZ lntoxlcatlon, consisting of 2O items
to be checked O, 1+, or 2+.)
. l+" Intake gJlq Oucpu!: Calorlc and fluld volume coneumed and
urinary votume excreted.

f f t;fn".f i t " ,r-'

Appendlx
1

ii ){ii;iF[B
A CONFIDENTIAL
3
 rl
rji
CONFIDENI'IAL

5, Cl=Lntcal OLS-ervatlgur Frequent descriptiond entered {n

the record of the subject's behavlor, conversagion, physical appearance
and other occurrenceg.

6. Televlslon Tape- Reqordlng: Not usually done durlng every

tlme perlod, but at intervals throughout the experiment. Coverage in-
cludes interviews and examinations by physlclan, excerpts of spontaneous
behavior, 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 to
additional practice effects during the test, scores should be 1O-2OS
hlgher at the tlme of full recovery.) .lust before being released from the
experlment, 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')ate
the extent to which he feels he would have been impaired in hts abllity to
perform 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 the
attainment of thls maxlmum effect" (It ls interestlng to note that the
estimates of the subJects ha'le been found to agree rather well with the
obJectlve indications provided by performance scores and wlth the opinlon
of observers preeent during the test.)
(c) Prlor to final dlscharge from the Volunteer Frogram, each man lrho
has 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 the laboratory staff volunteered

to take oral" doi6i-6FTiotn l+.0 to B.O pglkg.
Methodologl: Hourl.y observatlons of vttal slgns, neurolo-
g{cal examlnatirn ilA}neral behavloral status. Psychometrid iurr,
not echeduled. "u"u

Comqent: Only general lnforrnation was sougtrt and obtalned

from thls s.rie;;*T;[a ge.t*ruil.y unsultable for statistica]- treatment.

Appendlx A icir.{Fipr,nrtal .,'I:l

,+
 -.*:;:ffi;
CONFTMN i'nTiiutLLEu-*m u'ii;tft$IitF[[[
:!fis5

. 2. (C ) Oral Dose-Response lj-eries:

Dates: 12 Septeober , 26 wtober L)6O.
Procedure: Thlrteen volunteers recelved oral doses ranging
from 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 were
given 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.
Data lncomptete because of 10ng perlods between
observatlong and.cgnrnegE:
lnsufflcient descrlptton of. behaviorat Jhanges.
a

5. (C) Intravenous Dose-Response Serie,s:

Dates: 2L septenber 1!6O to 21 March t!61

Procedurgs: rbenty-nlne volunteers received intravenous
doses 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 oral
serles.
4. (b) Aerosol Chaqber Series;
Dates.: 1l Maich - 2) March L95L
P.ri}:crJure: Iiight volunteers were cxlr.: i,d io inhalation
"'d"
r:.1oses reirging, tor"-ii.f 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
pl.ete) 1s dif f icult. "tm; "ri;; r::'" r::::i,::"ll::':;t:,::' tffi i:i, rl'i."o"'_
5. (C) Percutaneous Series:

Dstes: 2\ ltay - 8 December L]5L

Appendlx A. CONFIDENTIAL
:: [l\Fi CELLTN:::
 CoNFTBENT

. 2, (C) Oral Dose-itesponse_ijeries:

Dgtes: 12 Septeober - 25 Oetober 196O.

Procedure: Thlrteen volunteers recetved oral doses ranging

from 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 were
given 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.
Data lncomplete because of Long pertods between
observati.ons and,corrnent:
lnsufftclent descriptlon of. behavlorat Jhinges.
a'
,. (C ) Intravenous Dose- Response Ser&s:
Dates: 21 Seprenber 196O to 2l March lp51
Sroggggres: I\+enty-nrne volunteers received rntravenous
doses 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
serles .

)+. (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: sinilar to that used for oral and intra-
venous serles descrlbed above.

o responees
"ffii; "::ffi ,::'"rlllii,::"H::':?t;,::' tl;iff rl"l,"o*_
v,ere '
plete) is difficulr.
5, (C) Percutaneous Series:
qates.: 2h Uay - I Decerrber 1!51

Appendlx A.
;;::::*'s-9I$qgMI4L,"
*--: u/ltr{0HLLEll *"-": ;ril'i.fr"ft$$$FFffiffi
 , \,,,. ' rr' ;
\"t"ii'[[i
a

coNFIDEl{ }-iAL , 'l

i
,
,,"i, i".,' t ''rii, ',ih'er

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 of
' BZ 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.
'r 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.
r-
Procedure: Flve non-smoker volunteers received lntra-
venous doses of flGTkg. Urlne collections lrere obtained and aasayed by
a chernlcal method for BZ oontent.
: Genersl clinical observatton was the only
method emproyea
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

t,,f
,:- *o ,rn,1 *!;-lsff,ffii,;
q r|!:)a 16 }",":i;:::ffi
lll,iil"tr:;i ;":l"lf"lruu'ut
either LSD or an at.roplne pla,cebo on the day he did not receive BZ. Drugs
were asslgned at random by a double-blind procedure.

Methodology: Baseltne phyoiological and cognltlve perfor-

mance measures wGie-Etaifi6d, and subJeltl vere"glven practlce in elmple
rnllltary 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 were
reached. .

- f
1., Nff n" ! | r'r.i
' rj

- --_ :,

Appendlx A CONFIDEI\TIAL .
A
v
 CONETDfrN]'IA***..

B. (c) ortl Dose-qgEaffir€F::-@*

ffi$i[gLL:::,,,*,,-
Late: 27 JulY 196L
Ploce{ure: Four subjects recelved oral <Joses of h pg/kg
to clarify the response to BZ in the threshold range.
lletLodologv: Similar to that followed for the earlier
dose- response s eries
Cotrlrr]snt,: Data collected was deficicnt in resPect to
contl,nuity and completeness of behavloral agsegsment'
,

. 9. (c) Jlhalatlon Series wlth Prototype Munltlon:

Wlnd Tunnel

Dates: 2 August - 15 SePtember l!61

a'
Procedure: Seven volunteers were exposed to. inhalation
doses" of from o.WJ vg/kg (estirnated retained dose)'

*v and oral dose-response

serles. Grenad"F*##ffi; ,:lll#":: :::ller
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 of
lnf orrnation.
1.0" (C) Aeros-g!-: olq] Conparis :

Dales: 5 ' 12 SePtember L)61

exposure l:r:' inhalation doses
!'.r:nr:e'"htre: t\aro weeks after
estimated at 6.O-""{rnO y.:'f*glkg respectlvel.y, two volunteers received oral
dosea of !.0 $g/kg to compare sevbrlty of response to BZ j.n known dosage.
Metllgdplo&yl stmiLar to that followed at Line of aerosol
exPosure.

Cgmq-e.n!: Thcsc subJects were the two whose case records

were consldered aaequate ln the prevtous aerosol serles. the indlvlduel
who 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 irst
exposureo. Results indlcated, however, that ldios)mcraoy to BZ could not

Appendlx n Htr
 ' " rl,'..
'., i,i I
t
r. i,!fi-'-,
CONFIDEN] IAL
Ilt'

Ue ttre explanatlon for the alypt"ul l"rponses to aerosol'and suggested

that retalned dose estinates could not be rel{ed upon to pred{ct re8Pon8e.
11. (C) Tfl.$ treagment studv:
Dates: l+ october - L4 November 1p61

Proceduge: FJ.ve subJects were given oral doses of l'0

vg/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 OevefoPed test of Time Estidation' were employed.
"ewfy
tleart rate was followed more contlnuously than in previous studies.
EEG l.ras also fo1lowed.
Quality of deslgn and data collectlon was better
!.g1r.urrenl:
ln some ruspe"ts-ilfrli-ln previous studles, but incomplete after 12 hours.
Restrlts r^rere adequate to demonstrate definlte though brief effectivenegs
of THA. Comparlson of responses for first four hours of the flrst test
r.llth same period of the second test revealed unexPected dlfferences ln
speed 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 of

from !.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 tunnel
qerles

g-onrnq+.!: Purpose was to compare effectlveness of larger

partlcles thao IIffi-3-O.B p sizes employed in previoue studLes. Sarnple
size less than optimat for meaningful comparisons, but strongly suggested
that the larg,er particles were lees effectlve. Protocols contlnued to
be 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 : .r
! fn [ '
r! 'i, ,\
lr IT:
:'
F..,. .. , q
Appendix A
'' '-borqnIDENTIAL
B
 ;' CoNFIDEN'I"IAL

?rocedure: thirty-onr volunteers were exposed Eo lnhala-

tj.on doses rangTffiTili*1.8-1r,6 vglkt:,, using the retentlon apparatus
and 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.

Additlonal personnel and equipment and refine-

,Conune4!:
ment of technlques resulted in much better records in this series than in
any previous one. Data was co-ngidered adequate for statistical treatment,
and ylelded confident estimates for the inhalatlon route. Inconsistency
of response qras sttll present, but thi.s was nor,r f elt to be def inttely
attribr"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 tve volunteers l^tere given lntramuscular

doses rangtng from O.5 to B.O ug/kg. The number of cases tested at each
dose level was as follows:

Dos e No. gf Subiects

TGre)
o,5 l+

1.0 o
o
2.O U
5.o 1
l+.0. 5
5.0 h
r.u 5
B.o 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 this
Appendlx.) A11 eubJects were pre\rlously unexposed Eo BZ. No treatment
was glven..
gonuneLt: Thie group of cases constltutes the most eatis-
factory source of data for detalled statistical analyeis. The case
records contain comparable measureg collected ln accordance with a stngle

Appendlx A
CONFIDENTIAL
9
 corv@rffi :€
':, niqh
nr\il
I ,.

U';l.l ,llo[ Y

prlnary protocol, whiclr has bG[ varied only slightly slhce its adoption
aE 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: 1}ro volunteers were given intramuscular

doges
"t B uelkil--
Metho4o_lo.gX: ltre ttandard BZ Protocol was folLowed, but
in addition performance on a varlety of outdoor military skills was
nreasured at lntervals. (See descriptlon ln Section III B) Motiorr plcture
documentation of pdrforrnance alterations was provlded.
gorule-nEr T-his rvas a pilot venture toward development of
mllitaryperformance assessmerrb technlques and in addltion provlded an
opportunlty to relate laboratory psychological measures to realietic "task
simple" *u."urer. Agreement r,ras excellent ln boEh cases, glving further
support to the. belief that behavlor in the field could be predicted, at
least 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 $B/kg
and then begun on tmmedlate treaturent with TIL\. three of them received
the THA orally in a total dose of 2OO mg. One nran was treated by con-
tlnuous iv Tll,A, receiving 5(A over an B-hour period.
^g
Itglhg_dg.!9gy: The Standard BZ Protocol was followed.
Serum choli.nenfielr$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 to
BZ 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 center
Itas 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.

rt

Appendlx A
tt;lXlii.n$$$fi1[ffi
 i -1.J
l .,-:,iJ:i iuit!
coruptoEN]-iAL i-' i
I.-,
'f

#e-''

Me."t&Agl_g.By: The men were trained in field communicatlon

technlques and subJected to a pLanned exerclse, which wae preceded by a
?5-hour baseline exerctse of slmilar rlature. (For detaiLs, see descriptlon
in 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 data
were 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 16

men for a-6 aayE. a_- UiEakdown by dose and number of days is as folLows:

No. of SubJects Dose (pg/.k8) No. of Doses/Subject

l+ o.5 ()
l+ 1.0 1
7
1.0 5
1 1.O 2
il 2.0 ,
US-ESgg,lc8y: fire Standard BZ Protocol was used except
tn the case of iiieren ;ho,receivect 0.5 1rg/kg rlaily, in whose case an
abridged version of the protocol wlth less frequent observations wa$
followed" Eoch dnt[y dose was eonsidered the beginning, c,f a neqr sequence
ef tflttn perln"Jll qs'1'41"gicir; uere unintained follor,rirrg t"ire Last dose
{.}J.,11

untll full remlssion of cumulative effecte (if any) was evldent.

Cqlgg:t!: Data collected was adequate to make preclse
egtimates 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 as
1.0 uglks,.
Lg, (C) Combllrej BZ;LSD Pilot Studv;

Date: 2) Augusr LJ62

, " _ -r-rT
.
' t L l -.:,1
,'"l.li
',irl:r.\illr
Appendtx ' id ''r'g
A CONFIDENTIAL -' '*

1r
rf
1ur dose of 2.0 ug/kg of
Methodglo-&v:TtreStandardBZProtocolwasfollowed.
9.c'glgtu: Although definite psychotroplc effects ltere
or simple
prodrrced, 1t coul?--il6f be said vhether potentiation, antagonlsm,
dosage and the fai lure
addltive combinatl.on was deftonstrated. conservative
hardly be interpreted beyond
to repeat the study resulted ln clata that can
eaytni that the t"o uguttts did not cancel each other out'
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
ts.=$hlg,*"&,9.!tg
ffi; .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-
thei{
a possiblllty again reised by the l"ack of relationship between
,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/kg
ot BV. 1\,ro of them receLved .r, ,rrrttu"ted dose of ?,0 $g/kg of BZ elther
prior 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-
placebos were given on the game schedule as the phveoetls-
;;;;-;;ric;j:
,mlne to the untreated Partner.

!1egl9&19.8:.: Ttre Standard BZ Protocol was follor{ed'

N::;:""'
ce f\ ffittffiu"n$ffiFtHffi
Appendix A
@-"* \i
iifi$;L:i
 ;'--
w@- -
ril lllt-ii , t
::':'r '

CONF'IDET{
ie

conrnent: lhe quallry of the cllnical regords ln thls

study 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
design ln al.l four subJectsr slnce two men declined to take the
"rosso.rer
{ose a gecond time. Dosage origlnally planned for physostlguine was found
to be lese than optimal and the lmportance of close regulation was atso
not anticlpated. In spite of these departures from the deslgn, the repults
were 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 volume by providing a
a' vtsual feedback oscilloscope-televlslon camera-video mqnltor linkage that
has as an lnput the subjectrs respiratory flow operatlng through a trans-
ducer in h1s face tr€sk. Changes in dtrectlon and rate of resplratory flow
cause 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.ows
a traJectory traced ln wax crayon on the glass screen. After practice
wlth 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 immediate
viclnlty of the subJeet's head. The wind tunnol was sealed off from the
grenade; 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 to
dlmlnish the severity of symptoms in these cases and to acquire addttional
experience 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. The
data was considered adequate to conflrm the effecttvenese of the munitl-on,
the retiability of the monltor syotem, and the correctness of the prevlous
egtimates of the ICTSO

Appendix A
ji 6 l

CONFIDENTIAL
r ,t l t

I iiii ii
It
I

1"
4J
 '(

CONFIDEhITIAL-
effi

\.rfilr '| Lt-u :

I
-

a'
APPENDIX B

cHHnrsrRY AND BTOCHEMTSTRY Or BZ (U)

[!Nf;t&$$lflEil
-s0Neffihfq,am
 CONF"IDEI.,ITIAL

A. (c) Froperties .
(c) - of benzillc acld, whlch ln its standard state ls
BZ is an ester
an odorlese, white, crystalline soLld. The melting point (f.) of the
free base ls f5h-167oC. The Tf of the protonated species or^hydrochloridg
ts 2r9-241oc" If the liquld free base is malntained at L?OoC for several
houre, decompoeitlon occurs wtth the production of C02, benzophenone,
benzohydroL, and snraller quantlties of other moieties. the botling point
(ru) is )20o6.
(u) Ttre free base is sllghtly soluble in water but is somewhat more
soluble in acetone, ethylene chlorlde, methanol, and ethanol, It ls very
sluble in chloroform, trichloroethylene, and warm dimethylforrnmlde. The
hydrochlorlde 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 sllght
dlfference 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 of
the 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 hydrolysis
nsr 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 cheurical
reactLone characterlstic of this claes of compounds. +-o Among otbers,
these reactions are acld-catalyzed and base hydrolysee, arrmonolysis, and
ester-tnterchange i,rJ.th the alkyl and/ot aryl groupe of other alcohols.
(U) More speciflc studies of the compounci in, terma of solvplysis and
pH dleclose that the half-period (tttil for hydrolysie of a 10-4M solutlon
ts 4OO minutes at pH p.B and onLy l.8-mtnutps at pH V.A: It has also been
determlned chat oue mole of eeter wlll combtne qrlth three egutvalents of
chlor{ne 8t pH 7.0 ln a perlod of approxiroately six houre. In chlorofqrm
aotutlon, 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 of
agent BZ ln solutlon. The root of the problem is, however, choo$ing and/or

Appendtx B
[fiffiffifl.&$$lFlHB
--*€*--
 qONFIDEN'il"IAL
'-*.- ti4 ru'
*-'r'
t; /{ l'l j.-t:*- , ,...- [-lJ'lt';!-r);(Ju-r
devlslng a reasonabty affiiff*?trr"d such rhar
"f'"-&;;;;*r"fitriviry,
fractional 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 certain
moieties obtained from oxidation and/or hydrolysis of the intact agent
molecule and the classical speetrophotometrlc determination in the
visible 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 the
other hand, the ester can be sat'onlfied)to sodium benzilate and oxiclizecl
bv HoCl to benzophenone, which can rather easlly be determined spectropho-
tometrlcally.9
(U) Kramer, -Q! al,lO t. an attempt to determine small quantities of the
lntacc compound ln blological flulds, concentrated the agent by adsorptlon
chromatography on silicate columns. The material was then eluted, combined
wlth the anionlc dye brornthyrnol blue, and the absorbancy of the resulting
solution measured at 600 mu.
(c) using still another anionic dye, tropaeolrn-oo (p-(p-anillno-
phenyl-azo) benzenesulfonic acid), Edberg and Kondrttzerii have determined
BZ spectrophotometrlcally (51+O *fr) at concentrations as low as O.]-0.5 pg
ml- r. T'he mettrod is, however, not adaptable to tissue. One other disag-
vantage is the hlgh "blank" readtngs obtalned ln the presence of certain
pseudo-aromatlcs, 6.g., nlcotine and purlnes.
(u) Stltn12 has recentl.y reported ph percent recovery of the intact
coupound by vapor-phase chromatography of solutions of the agent in rat
urine and human blood plasma. This procedure has not yet been adapted to
f 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"s
meager. Korrdritzer,'/ uBlng Ii'- labeled compound, has lnJected doses of
L,6 ng/kl-1 body welght into male rats tntraperitoneally. Ttrirty-slx and
one-hal'f. Percent of the total radloactivity was recovered ln the urine
wlthln 2l+ houre following administratlon. Only B$ of the urinary radio-
active material was present as BZ per .3e" Radioactive materlal was bound
by cerebral tissue L! minutes after lnJection and after 24 hours was
stlll LO$ ot. the maximum value obtained in the brain.

Et6il n.{: r'qill

-'l'i] 'i:il
q FF.\

Appendix B
E|[Fn--
CIrj'11
CONFIDENTIAL--...
''1 ),li:'l
' ,,1
j

I
 @*'*:,jGUuqfiit
i+.-..-s#
H$$t$t[U
(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
"nt- and.f or hlr-potiralarrric region in the floor of
the third. ventricle. )+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) ll.r"h16 lt."
Using +.he tcchnique aescribecl by lieirnber8, e-L jayg!,t5- l,he llver
. c,lq:J-etecl pr.ellminary sturlies on the meta.lrollstn of RZ pcrf'usirrg
o1' aclult ma-Le rats wi'bh a pert'rrsate con'ba.j'ning f .32 W'ft conrpound'
' Usjng a modil'lcation of' 1,he Orange IV co].orimetric B.ssayr"\'.,the " this investlgator
forrnfl. 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
.'..peyfusate
both the
alcl 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, prior
t9 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 is
iiactivatecl'' 'bo
to t;5e coenzyme A clerivative (benzilyl Co A) prior 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 bioclrenlica-L mecharrj.sm of ac'Lion of the

fev studies 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

Appendlx
::sofirusENr[aH- [$fi$ffifl,$$$$trHHffi
w&'
B
ry*t*
 @NFIDEN:$ TAL
: --- " i; A I't ' l i 1- ;' r.r ';; '-j*
**-*-''"-..*"-..-:.-.:".."-":.:-
tr'',,-- lurnover-of phosphatidll- !- serl"ne'
compounds but have no ,u"ti,Iitr""CJ., P12 uptake by the lat'ter
Both atroPine and BZ were founcl to increase the
'subs tance.
(C) Other studiesl8 1ru.r" indicated that BZ added to equine blood serum
unesterified' fatt'y
results in the pro<luctlon of isomerized, presumably
chrt>matography as conjuga-
aclds, whieh have been tdentlflecl by vaporthephase
lsornerism is of the cj"s-trans
led, unsaturated fa!!y acids. Presumabiy
a concerning one possible
varlery. so.tocorifi?''";;;-leads to splcula'ion
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 'xidative phosphorytaiioi' In adclltion ' J6 pet-
cenE of the total phosphate ln mitochondrla is
associated with lipid phoaphor-
ous19. Presumably the structural lntegrity of thetoe;rzyme-fiystemsr
sequencc
oxldationo'
could thus be corpro*i"ed by Bz, thereby llading lncomplete
factors could result in
uncoupling of oxtiative phosphorylation, etc. Such and not in the least
the blocking of many essenti.at biochemical reactions, e'ergy assoclated with
those endergonlc reactions r"q.rriirrg the Gibbs' free
enzymatlc hydrolysis of aderroslne triphosphate'
(c)oEherresearchershaveproduceddata-disclostngthatBzblocks
contractlons of isolat?l-u
serotonin-, nicotln-, and a"etylciroline-inducecl as low as ! x lO-a
guinea.pig ileum. Tlnls occurs in medium concentrationscould possiblv be
pg/ml-r. Again, the centraL e.f fectg of the conipound of psychoses'LJ
interpreted in the llght of tlooliuy;, "serotonili-t'ypott'esis
(c)Arefresh{ngbiochemlcalapproachhasj.nvolvedstudiesofthe
actl-on of BZ on the respiratory rati;; of K+ and electrically
stlmulated
from the eontrol
rat cerebrur "orl*;-.A{,'22--wilt r. stlmulation no decrease
range of 5 * 19-5 to
ratio was obeerved over an agent concentration response to electrical-
,-"'io:5*.-"ii-ao*s, however, trl0ct thepursls
respLratory
second-1, 10-r2v).
stlnulatlon of the cortical'srices (rao

(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 he employed rat brain homogenate contalnlng adied Ugl*, Na+, K*, flod..
adenosine trrptrlspt"a.-ionl. fi;.* and ATP weri added, since the "ac!lve"
tranEportoflonsaeaphysJ.cochemtcalprocesshasastandardfreeenergy
therefore, that BZ
change grearer;1";-"urf ( ro>0). It was.believecl, of ATP'
might lnhiblt the enzy*ic'hyclroiysis of the termlnal phosphate

lr ResplratorY ratto - /dry glhour_!gt. stltlll!"d :9tj1I

aroms 02 uptake
g/hour for "restlng" cortex
*.--._.-.---;-:;;.'^J.^lt^^9}^U

"tJms*6 "pt"k-rury

Appendlx B -* f. ItF! tFl lFn ----' Ffinnry |{,,Qffr,Tflrl'Tl

CONFIDENTIAL
 g F(DEI.{l'lAL . * [tuuffil"A$$ffiffin
,eB$s*irffidd

Boldtrs experimenrs falled to show any decrease in inorgahlc phosphate in

the homogenate medium, thus precluding the inhibition of ATPase act.ivlty
by the agent.
(C) On the basis of olher scattered data, one Ls temptecl go speculat,e
that BZ could involve some other unusual cnzycre systcrns. l.tcllwain24 has
found Ehat nuclear htstones inhtblt thc restorative action on cortlcal
electrlcal (respiratory) activlcy of plasma protein fraction fV-1+ (Cofrn)
afcer the brain slices have been kept aE ooc for !-lJ hours" tr1g625, in
this connection, has reviewed brlefly the liIerature relating memory to
enzyme induction and riponucleic acld (nn.t) blosynthesis and degradatlon.
Further, Ir-vtn, gt- al,ca have shown that nuclear htstones (isolated from
thymus deoxypentose nucleo-protein) possess RNase activity. The idea,
therefore, should not be abandoned that at some point along these diverse
blochemical pathways and feedbaqk systems one may fincl a slte of inhibltory
actlon by tsZ sufficient to produce the diverse neurophysiologic charrges
knosrn to occur.

Appendrx B [$ftxfrH-f{$$n$[f,ffi
-8RNtllRFNfil4ru
 (u)
!. 1. CRDL Sp Pub !-2[J. EA 22TT. l\ Ijurarnary Report as of 15 Marc]r
.:. rq6r (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. Tech Memo 10-25. Quarterly Sumnary of Progress, Directora'l,e
CRDL
of (u). 31 December 1960. SEcRilT Report.
Researcn
[. Kosovcr, E. IU. I'4o1gcular Biocheinistry p. 125. ]'lcGrar'r-lli11.
Ner.r York. L962.

5. Iline, J. Physical Organic Chenr*istry p. 255. McGral.r-l{i1l-. Ner,r Yorlt.

1956.
t'
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"ition
p. 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; Some
Chemlstry 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,, l,,cl,er.irLiii:r"Linn cf BZ (U). January 1.963" fOiTFIDlilflIIAI'
i,:t;'.irii*c cn 3Z;
Reporb.

12 Ellin, R. 1. CRDL Tech Meno 23-27. The Use of Gas ancl Liquid
for ttre Quantitative Determination of BZ in Rio-1-ogical
Chrrornatogra.phy
' 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 Isolaterl
Perfused Bat Lj.ver. Am, J. Physlol IgSt 5n-6ff (fgi8).
Appendix

ffi8fipffiH
B

85ffif;n"ft$$EFHf,m
JLW$@F: 'r'
 .
\)1rl{::'
)llt'ilL{},
CONFIDEI'd"TIAL ," ri i-l"i:-; i- i
., :'
'.

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 Progrcss R.:ll,,rL f'or Physio]og,y
' Division, 1" July-J0 Seplember f-951 (U). Scpternber L96I. COImIDmXIIAL
i),rnarl'
r\u1Jur r/.
5

IB. Tech l4erno 10-30. Quarberl;; S,lmn"'lry of' Prr:gress, Dlrectora.te

CRDL
.. 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{emo11-3. 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
{-. \.,
l. , I

APPEI'IpIX C

FIGURI]S AI.JD TABI,ES

 \rUrri I'l-'''
(,, P
;-itOBIT ANALTSIS NOn 1
r t'
1,,
iilill
t_ illl itil
il
j-tl
!

l,lii1 i1 ifll li
l,_ li,ll t$li lii
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.-,t* 1r

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(m'cgrrkra) (r.eAe) t-
illl lil illi
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ll ri
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 I iJ-lANAi,iJi! No' 3 LU I\ f 'tU Ll\ i ;nL
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i liiil,iiii,.i .i.. l,illililii.l

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ii
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Problt - -2.26 + 9',2 Lo[ X

Y. ilii q
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l,
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't-lil: o
:l',i
959.' Conttdsnce Llmlta
,F, an(F) lower llpper l;r
*1,-.
iir
1 l.LLlt 2.6555 L.L6o ;ll:
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N

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MQUIV, D0SE (rncg/kg)
A*PPENDIX C
 ,.T ANALYSIS No, h
C0i\FlDti\ ifAL
lllrrl
ii riil :1,-l-l-l-:ll
'ili --r i*hhlr*rli'l
lesponso ll I 1.1.
t-r.l 1i"f
n tit r-rtl [jt1\]'fifr" $i
lrlterton . TRf . 7.0 (maxfunum)
e
H 'j 1" ,'l: -F. 1{ ! ;lji$F,r#ffifi'Fntr
'-' :: :.: I i

3ampl"e etze - U.6 (a11, routea comblned) s a

I lj rl: L1.-+;
'''rl"
1

i-
I ll t,
tl
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I
llii
Mean Doso Range Besponoo lili
.t

(*e/te) (ncelte)
L.l-
iii
l

iiir iI .l-
/,
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0.9 0.L - 1.0 o/Lz rli
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1.7 1.0 -. 2.0 o/L2 I

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-l-
3.1 2.0 - 3.6 o/\2 I
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I I

I
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li I
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3.9 - u,3
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t

5."1 \,5 - 5,3 o/L2 _l I

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i

t I

tl
problt, y, . -,672 + 6.LS Ine X
t/;
Standard orror of slope - L.59 /
-t
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95S confldonee Limll,e -l-t-i.-
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li il
t-. .3.$o2\, 2.0698 rl ll
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jo. 6.879
l

lo 5,98) 7,9LO
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lL .12,152 ?,08L 2O,Blt6' I
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1

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rii
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APPENDIX C
fV EQWV. DOSE (mcg,/kg)
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lili
; iTllllit
lli i
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1
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lril i -l_ lll tiy
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i rtj t: -;-'-/-i-' I -l- l--:

I I lili ir.l i.rl:tri, ti ''t
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l,,l.,r
riil lllil illlrrtl
I

r'i i'i
t"i1!
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li|
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Regreeelon Equattonr i-.ll

llit '-'rl'
.;'t;t,
..:-: i ll
rrobtt Y - -2,98 + l.gg tog X .t,l i:i lr, il :lrt
l.;
I tl
l
f,i lll .t;i

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P ED(P) lower upper -t,l_ iti ,-l--.,-_

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APPH{DIX C
,c (mg-In
 t,ltr ANALYSIS No. 6 LUr'if llJ+f i i,'iL - - 6

rilr
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iiir i: ir ili
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I

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ir;l il, i;i _ts _l I-r l-l-

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/
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j L, r*.
- /-'.-'::- 1-.i-l
l.irl
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1-1 I

robtt y. _9.67 * 6,gg'LoeX

I

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I L

tandard €rror, of alope - f.i8l rl :-i:i i.

rl
I

tr
::1 i-

i'lr ...I
I
I
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I 1'{l

P FD(P) Lower u,pp€r lili

:11
t: / _t-
. ill
e
rtl
1r
L 51.o5t 31.391 107.39 J.Li
llil
i1,

6 89.98 66.77 :-n-,26 tiil r1

o 105,03 81.51 l-30.53
I
I ri
iri
L-

il
i-

0"121.82 1O2"Bo 151"5b

ti1
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h 173,11 L2L27 2Li7.1L

lilr
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227,63 t 3o.5L 396,95

lr, lrll
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---l-i--i:-'-I t-

lil 1i ir i11 _ t_r__.1 .

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LdirrruENTIAL -90 -, .6

APPD{DIX C
!- / c f (nrem minr/n'r3)
tlit I
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I
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,., l:o

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. ..,,.i

nple alze .36

ean Doge Ranga Responao

'frT
5v Lb-71 o/6
BO 7I-BB L/6
ii
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20 110 - L26 L/6 o
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167 - 6/6 o
LO 311 \o
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a. N
I
H
0<
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c)
q
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E4
H
I r ,i+ 7.0b tog X !
q
lblt, -]Q.QQ FJ
H
pa

rndard error of alope'. 2.022 c0

O
a
Ai

959.' Csruttdence Limlta

ED(P) lower upper

62.99 33.99 11.6. ?L i11ll

!t, Q

!"i,, l,f,
r ' r-. I

Te
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111" 53 9L,77 110. L5
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\3t.72 lrlrr.56

a
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?n{DIX C C. T (mgrn mrn/m3')

 c0 t\ l- I I it ry116t
, r
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. JIT ANAI,TSIS No. B
ri N
I

iIl
I

il i" li,
*fi--F t t_l :tri+ lliil rlli ll,J
lrl lii i
iit
rpon6o
Iterlon . rnr)t (ruaxlmum)
I

I
llr itt
i.i
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,#
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il Lri'l 1tf;
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rll
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ll_1'] lt lr iii i
rll
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Il il1l lii tjli l:l - -l -' -: -rl -l-l_i-:_t,
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li 'ill
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ii
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a
ll
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i1
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f ,, Ii -' :-
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i _t_', /. r-l i-. i I : ; l liir ;l ll
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183.05
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