TI-IIS T)OCUMENT CONTAINS _A_I_ PAGES, COPY NO. _j OF COPIES. AS A VEHICLE FOR INCAPACITATTING AGT:NTS Prepared by: 6 24 December 1971 This report has been prepared by as a part of a Governrnent Contract. The views expressed are those of personnel and not nece-ssarily those of the United States Gover=ent. TABLE OF CONTENTS 2a@Le Protocol Statement . . . . . . . . . . . . . ... . . . . . . . List of Fi.-ures and Tables . . . . . . . . . . . . . . . . . . . iii Problem . . . . . . . . . . . . 2 . . . . . . . . . . . . . . . Discussio-,i . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Potential Applications . . . . . . . .. . . . . . . . . .. 3 . . . . . . . . . . . 111. Physiological Considarations . . . . . . . . . . . . . . . 4 A. Introduction -- Nature of the Skin . . . . . . . . . . . 4 B. Theories of Penetration . . . . . . . . . . . . . . . 5 C. Substances "Carried" I . . . . . . . . . . .5 D. Penetration Studies . . . . . . . . . . 2 . . . . . . . 6 1. Stratum Corneum . . . . . . . . . . . . . . . . 6 2. To the Bloodstream . . . . . . . . . . . . . . . 8 E. Fate and Metabolism . . . . . . . . . . . ii F. Local Reactions and Toxicity . . . . . . . . . . . . . 12 5 G. Physiological Conclusions . . . . . . . . . . . . . . 14 IV. Other System Factors . . . . . . . . . . . ... . . . . . 16 V. Recommendations . . . . . . . . . . . . . . . . . . . . IS References . . . . . . . . . . . . . . . . . . . . . . . . . . ig I-JST OF FIGURES Pag Figure I oection Through the Skin of the Hurnan SI--oulder 4 LIST OF TABLES Table I Derrnal Penetration Rates of Various Mixtures. 3 9 AS A VT-HIC-LE FOR INCAPACITAITIN.G AGENTS PROBLEM To evaluate, especially from the physiologic point of v4ew, as a vehicle for personnel incapacitating agents. DISCUSSIO14 2 1. Potential Ag2lic4tions For Inc@@@@ lis a chemical with the rather extraordinary proper- ty of penetrating skin rapidly. The zF,L-,in, long thought of as a virtually im- penetrable barrier or as an only slightly, slowly permeable one, i's easily, quicl.-ly, and r-eversibly breache2d I Furthermore, many chemicals. when dissolved can cross the barrier along with Such a proper:y lends Ito consideration as a poszible means of deliver- irig an incap@Lcitating chernical agent via the skin. Those drugs which i-nterfere with a person's state of consc;.ousne5S inducing los.- of consciousness, panic, disorie-ntation or h2allucination could conceivably be ad,-Lninistered, as well as drugs which incapacitate by causing motor r-'ysiunction or muscular paralysis, or those which incapacitate by producing somatic preoccupation such as itching or burning. Since many incapacitating drugs require-fairly critical dosage, the usefulness of a ncapacitating agent mixture would 6 93 probably be 'limited to individuals, where the dosage could be more carefully controlled as to quantity and site of application. In a crowd situation, uniform dosage vrou'-d be quite hard to obtain. -z- CD 0 Ill. Rtiysiolo@@ical Considerations A. intradLictiOn Nattire o@ the Skin. A pr,'_rnary function of the skin is protection of the bodf. One way in which it' cloes this is b-f serving as a barrier to penetration of chemical s -- harrnf ul or o,h,--r%vise2 -- .nto the body through its surface. it is a formiciable barrier to suc,a penetration. For exarnple, the epidermis retards the diffusion of lovv rn:@-..ecular weight, water soluble nonelectrolytes (among the most diffusible of substa-,ices) by a factor of over one thousand times. 7 ,itrcrtum c2orneu;n O*- #,O@ 16 4;!,00 4 e "41' Vessel Pcipillar)f I ;-f a,rar t,it 2 of C(OFMA Fig,-ire 1. Secti-on through the skin of the human shoulder To get from the surface of the skin t,) the circulatory systern, a substance n-iust first pe-ietrate the stratum corneum, or horny layer of the epidermis. This is a thin layer of dead, keratinized epithelial cells appro3:-i--r-nately 10 P 2 thick. Once this is pas5z,,d, the stratum Malpighii, or living part of the epicierrnis (100 p or ao th@.ck), then the papillary part of the derrnis (100 - 200 @l thick ir@ rno st places) must be. traversed before the capillaries in the derr-nal 3apillae are reached. The stratum corneum constitlites by far the8 L,najor part of the skin barrier insofar as resistance to diffusion is 7 concerned. if it can be breached, drugs an gain entrance to the body via -4- ttic sl@,in cLii-i--@nating the need to administer them orally. by injection, .)r by other routes. 11. Theories of Penetration. e human ski lis larf,-ely Ttie actual rnechansm of penetration of ti n Lini@now,n, alt@-o2ugF. several th,-ories have been advance-d. There is little or no c,.ridence in support of any of the theories, however. According to the r'nosl widely held hypothesis, the molecules \replace molecules of bound water in the stratum corneurn. @bonds are less tight Llian 1-30H - HOH bonds and, therefore, temporary dissociation, allowing 2 chernicals to pass through, ;vould be easier. 7 In order @ to allow other substances to penetrate the stratum corneum. saturation of the inler- molecular spaces may be necessary. As says, "it is almost as if the pezietrant is conducted through the horny-layer barrier by remaining .d.issolved in a continuous channel \-hich occupies inter-2 molecular spaces. " This "opening up" of a pathway t@rough the stratlu-n corneu.m occLLrs for a limited time only; le ave. s the stratum corn-2um open to penetration by other chemicals for 1-1/Z to 3 houis only..f It is suggested thalt by the end of this time the saturating quantity of iias either diffused aw2ay from the stratum corn-eum or beer, absorbed into the circulation. ,gh concentrations are needed for effective penetration. Thi-s may be a resilt of the 1:2 or 1:3 associational complex formed wth water. A 75@-o or greater @has space remaining available for association with tissue water molecules -- they can be removed from7 t'@-le stratum COrneum and replaced C. Substances "Carried" Various investigators tiave conducted experiments in conjunction 5- witi-i'a @.vide variety of chemicals in ],opes of getting them thro;tgh the skin barrier. As a general rule, low molecular weight, nonionized chemicals pass through the most quickly, those which -ire ioni7,ed and/or of higher molecular weight pass through more slowly, if at a-.1, and substances of high mole2cular weight such as insulin and ragweed al'.cr--en do not pass t-@trough at all. I - Some substinces which have been tried and which do pen,@-trate the stratum corneum It should be stres,@t!d that nearly all of these studies measured penetratio.1 only through the stratum 2cornekim or into the skin. They do not imply penetration ;.nto the bloodstream. Indeed, many of these substances, including- @have been found to penetrate only through the stratuna co:cneurn into tt.e epidermis ar.,.d derrnis, where they may form a reservoir. Some, such as imay remain in 2the stratum COrneurn for the most part.' D. Penet:r-a,tion Studies. 1. Straturn Corneum. There are two main f.-,ctors to consider in the penet.-ration through the skin barrier -- the speed of penetration and the quantitative amount of penetration. Neither has been establ;,ghed with any degree of precision, but -some figures are available. fourd that 1. 517. ---@penetrated (as established by serial stripping of the skin's horny layer with cellophane Lape) to the 'basc! of the horny layer i,-m one minute. The liquid was applied as a "Pool" by rneans of glass cylinders taped to the baciz of male Negro2e-,s. lie alsr, found that lin a glass cup produced whealing as early as two n-iinutesl after application. For whealing to occur (most probably due to 1-iistamine liberation from the mast cells) penl-tration below the stratum corneum rnu,,,t have occurred. These results were obtained with 2present in d,--p@h above the area treated, how@--ver -- r-ot with i, spread over the skin or a--nplied in small quaritities. Ion the back 2-nd spread it with a glass rod. They noted signs of reaction (,vhealing, ez-pecially around the hair follicles) in 5 to 15 minutes. The difference2s in whe;:-Iing times between work may indicate that tl--t absordtion time is a function of t@e arnount. enabling quicker penetration than thin layer. obtained anesthesia of the eardrum (which has a stratum corneum 2 just like any otaer skin area) sufficient to allow rainiass myringotorny (cut- ting of the ef-rdrum) within one rninute after wiling the eardrum with In another study, penetrated to the base of the horny layer --n 20 minutes. In ithe time was 55 niinutes, and in II 20 2minutes was the time for pe@rietra-ticn, These results ern- phasize the need to use high concentrations @for rapid, rnaximun4 penetration. Published stitlies on the quantitative penetration ihave beer, almost nil. iin gel form on the elbow and let it 0 stand for 30 minutes. By then wiping off and weighing what remaine4@i at ',he 7- end of ihat iirne, they. calculated Lliat 25-40% of ihad been ab- Sorbeci, This was obviously c@ @-,-lugh determination only. ',eight hours af-,er dermal applica- 4Co,A, that ZOI@, of the applied dose was still in the epidermis. He did not ioentioji mhcrc or how the remaining 80% was distributed. These -.-vo studies dernostrate that dermal application @is lo ZSS',Lrance that all of the compound will penetrate the skin. Furthermore, of -Li%-at !)ortion which does penetrate, s,)i-.ae may remain iri the epider:-,Li2is for a conside--able length of time. These studies were @alone; chemicals iiczarz-il,d " @may or may not behave in like rnanner. At present, it would '@-e airnost impossible to predict what the behavior of a @iveii rhernical t3 2 ajigy1t lwould be with regard to ocrcent absc;-@-ption or penetration rate without acLua'-Iy running tests on that particular chemical. -,vhich has been little investigated is the location of the skin to ..,,.@,,!@rated. It is known that, with regard to such r.-iirgs as water diffusibility, 2 arels of the body are considerably more permeabl,@ than others. F6r scrotal skin is ronsiderably more permeable than abdominal skin. 7 ;,rL' se-ve.-al variables which may be at work. The sltin it.-elf (epiderrnis tcrrr@is) -%,aries in thickness, and the stratum corream itself may vary- 2 @',Ilor LI-lic.,neSS or structure. Other than on the soles of the feet and the oi LI-Le liands, where the stratum corneum is considerably thicl,:er, but @liffusivity, the stratum corneurn varies '-ittle in thi,ckness. It v;lr,,i in nature, however, as in tb'e forehead, where there i2s a less orderly, :",Oro open arrangement of the cells. 7 There may also be some difference- L'@ici@zncss and composition of the stratum corneum among various for example, Negroes vis-a-vis Caucasians. -iO t]-te Bloorlstrearr. %to,it of the previou:,;Iy discussed studies of time and r9ate of pene.tra- "On Consid(-red the stratum corneurn and epiderrris only. If the site of AIML ----------- act,lon of the Jjcarried'3 drug is the epiderrnis file. all of the major factors ]lave been cOnsi@@ered. 13ut drugs which have the brain or body organs o2tlier than the skin as sites of action must igO not Only through the straturn ' corneurn. but also through the rernainder Of the epidermis and then a portion or Llic dertnis b,f,,r,@ they rc!ach the blootistreazn w.Llich can transport thorn. This is where rnay fall d2ov,-n. studied the influence Ion derrnal clearance (the tirne re- qui.red for the circulation to rernove injected substances frorn the derznis). Fluorescein, a fluorescent dye, was injected intradermally -- 0. I rni in saline, and in 259/,, 507a and 750/, isolutions2. The clearance time for the control (in saline) was I. 8 hours and the times for the solutions weze 3, S. 5 and 18 hours, respectively. The effects Ion dermal permeability were studied by measuring the penetration rate of 101,) aqueous fluorescein through abdorninal skin which. 2 had been stripped of its epidermis. The results are surrirnarized in the table below. TAB LE I D Saline Control Penetration rate in p g/cn-l' /hr. 79. 6 17. 5 1.3 2 0. 6 In the case of seems to inhibit or retard passage through the dermis. offers no theory or hypothesis to account for this, stat- ing sirnply that "the diflusivity of connective tissue was probably being de- pressed One qualification, however, is applied to the intact s4kin would probably not attain such high concentration's in the derrnis as were used in these experiments, so that derrnal clearance anci pern-icability probably would not be relarded as much in normal use as ,@v@i sobserver! under the experimental conditions. For incapacitating agents which act on the brain, the most irnportant considera- Lioll is not how fast penetrates the liorny layer, but how quiclc@y-it or adrug2 ad--i-linistered b' -I )reaches the loodstream. usii-i taffged jgiven derrnally. found traces of radioactivity in 9 blood drawn as early as five minutes @was applied, but the level did not reach a rnaximlir2n until 4-6 hours later, reaching a plateau where it rernained for some time. One other published experiment, v.!hich gives time:s and blood concentrations for humans, showed one hour after admin- istration, but the peak level (approximately twice the one hour level) was not attained until four2 to eight hours after administration. These two experiments It can be seen that a measurable imay penetratf- to the bloodstream iya as little as five rninutfs. Whether or rot chemicals ll.carr'ied" by ican enter as rapidly would have to be determined experimentally. Cther substances rnay or may 2not reach the bloodstream this quickly, depending on several factors such as molecular weight, configuration, solubility in tissue water and Upids, and reactivity to tissue components. The in blood keeps building up to a peak which is onty reached after several hours; such behavior would not be' acceptable fc>r most brain-active incapacitating 2agents, for a dose powerful enough to incapacitate in five minutes would continue :to increase for several hours, with serious and quite possibly fatal results. Unless the therapeutic ratio* of the drug is quite high. safety could not be insured. This, however, Ratio betw4een the lethal dose and an effdctive dose. I 00 - assurries tiia-- the chemical agent would behave the sarne Nviiich may not be the case. There is a possibility, b-it only a.@.@lit one, that a peak concentration of an incapacitating agent could be reached quickly. In Lliis case, maxirnurn effect of the drug would appear soon after adrninis- trat2ion and a lower, safer dose could be used; the initial incapacitating dose would be the maximum dose received. One report, showed apparent worthwhile re- sults in feed'-ng through the skin Such things as glu-cose, carotene (vitamin Al, vitamin and some arnino acids 2 B12- were absorbed in fairly significant amounts, as signified by blood levels and weight gain. The blood glucose level war, 1657a of the initial value within 30 minutes application. The net elevation at that time, which does not account for any glucose v@hich may have already entered the 2 bloodstream and then been metabolized, accounted for about 31o of the dose administered to the skin. E. Fate and Metabolism The metabolic pathways takes in the body are still relatively unknown: Gas -chromatographic and radioactive tagging techniques /show that it is excrete.:i as unchanged and as two metabolic byproducts --2 dimethyl are excreted in the urine; leaves the body via the lungs. Fecal elimination is negli- gible. I Urinary excretion accounts for most of the removal as the lungs eliminate only 1-310. Most subjects by the dermal or any other route have a 8 characteristic "bad breath" said to resemble This is caused by the presence of the wi@,c, h--ap-p-e-a--r-s-i7n- the A rather special case, breath soon after administr;Ation and continues for Z4 hours or so. L a, a I.R c. P-c-t-i 0-n-s-a '-' d--T-o --' c-' t L' applied derrnally in the concentration typically is accompanied by transient burning. itching, and erythema (reddening)2. Its e.-otherrnic reaction with water causes an increase in skin temperature. Iii a sigiiificarlt number of cases, may cause whealing. This is assumed Lo bc aL result of histamine liberation. A study of over 1000 C;erman patients who were given dermally for a IS- minute perioc@2 per application yielded the following data on skin reactions: 6 - 87o showed no local reaction; 3301, had a slight reaction (warmth, itching ar-d erythernF-); 565c, had the "typical" reaction (burning, itch'-ng, erytherxia for 3 - 4 hours, a-2d occasional local tirticaria); 2 2 - 57. had a more severe reaction (dermatitis, urticaria, and occasional vesiculation). in cnly about 3.5'7o was it necessary to discontinue therapy. This was due to the local skin reactions which disappeared upon digicontinuation of the treat- i,nent. There were sometimes complaints of transient nausea and headache 2 g those The "bad breath amon @@ but no serious cornplicatio-is. was noticed in most subjects, and 501a or so reported they could "taste" the .1 In all of the studies done on humans (including over 4000 individuals in one)of the studies) )no serious side effects have been 2noted. The terxi- porary effec:s were those noted above, and no permanent changes or damage have been reported. tested sersitivity of the conjunctiva * to drops of Two drops c-aused only temporary stinging and burning, and, in some cases, The membrane covering the anterior eye and the ir-ner surface of the eyelids. 4 12- rnild injecticn (congestion) of the conjtinctival vessels. These effects soon disappear@-,d. if dropped onto the eardrum, may be painful. but will cause no long-lasting or permanent damage. @was withdravzn as a clinical drug in the United States in 1965 by the Food and Drug Administration because of reporte2d lens changes in dogs which had been given up to 5 grarns per kilogram The FDA has subsequenlly allowed resumntion of clinical testing.' There was fairly extensive in hurnan!@ in this coiintry before the FDA ban, has- been available as a prescription drug No evidence of any human eye toxicity due to 2 has been observed , )even in the highest experirnental doses given (I g/kg per day for 1Z weeks in one study, @30 g per day for p to 21 months Z7 in another). Rhesus monkeys @have been given I - 3 ml of per kg orallf or 1, 3, or 9 rnl/kg de-ycnally daily for periods of up to 18 months and no toxico'logic or path2ologic changes have been seen, other than skin rea@-tions. @Monkeys have been given intravenous do,- - as high as 4g/kg with no deat-is. No estimates of an LD have been made for monkey or man, but in view of 50 the high exp-zrimental doses that have been given already, the LD 50 would be far higher than any dose wh2ich would be given for ptizposes of "carrying" an incapacitant. Substances given in combination howeve--, may result in an altered toxicity. reported an interaction between alcohol in 1967.. He claims to have found increased rates of mortality in rats given The dose lethal to 500/o of those to whom it is adrniristered. 8 13- Ili-ii doses lafter previously having been injc,:tcd with alcohol. I-le also said he found more psychori-iotor impairment in humans given alcohol (or-.il'-y) and (vla the skin) than woulcl be expected from alcohol alone. This interaclion sliotild be investigateci further !is 2 to be considered for uso in inc-.ipacitation sincc there could )@c complic-itions if the iwere used on drunken subjects. Interactions between various drugs other than alcohol @should also be investigated further. One grokip of investigators found that creased the t:3xicity (as reflected by a change in the LID 50) ladministered orally to rats by a factor of up to six times. Thus, there is a possibility Icould facilitate the body's absorption of drugs from sach sites as the gastrointestinal tract. Such facilitated absorp- tion could conceivably cause an otherwise safe dose o--' a drug to become a serious or possibly fatal dose when given 2 It can be seen, on the basis of the fairly extensive woz-k which has been done@,' I applied exterr-ally in small quantities can 'oe expected to have temporary, local effects causing some annoyance and dis,@-omfort, but no Ion-,-term or p,--rmanent damage. Whether or not this would be true of Imixed -with a given chemical agent would depend u2pon the nature of the chemical and how it acts in conjunction @ Such knowledge would have to be established by experimentation, using the specific chemical agents to be considered. It would be quite desirable to have @,-urEher data on the ' interaction of alcohol as well as any other drugs which potential subjects mig@t take before or adrninistrat-'-on. 0. Physio opical Conclusions. F'or use as a "carryingil agent for incapacitants, Iwould have to be used in fairly high concentrations, probably To assure useful speed pt penetration and to ensure penetration it would have to be applied in volurne, perhap5 one r.-il or more, as show7n by various investigators, 14- can fairly well be ruled out as a 2-nearis of quicl,, delivery for psychatzopic agents, or any other agent with the internal organs as a t.irget. The chances are very goocl that any agent deliverf-,@l would not reach peak blood levels for several hours. For a drug to be effective quicl-ly (s2ay, reaching the blood in significant amou-.-,ts in five minutes) it woltld have to be administeree as quite a large dose. Thi5 is because, so far as is kr-own, only a small percentage of the adrr@inistered dose will reach the circulation in that initial five minute period. There are :oo many variables to be c@:rtain of the fraction of the delivered 2 dose which is likely to reach the target organ. This is especially critical for dosages of the psychotropic drugs. Whether all the material ;ands on the skin, hDw much remains in conta.ct with the skin, how calloused or "tender" the subject'.s skin may be -- all may affec-- dosage and absorption. Such possible factors as individual variation @ll penetrabil2ity" and possible insexisitivity to the "carried" agent also enter in. All these factors would tend to clirninate rnost "brain-active" agents from consideration be- cause of their relatively low therapeutic ratio. Incapacitation by somatic preoccupation is a major remaining area. Intense itching or burning can be qtiite incapacitating. Applied in the conventional 2 manner, skin irritants such as itching powdr-,z z:an be removed by washing. Icould cause the skin irritant to penetrate into the sk-kn, where a reservoir could be formed. Once within the skin, vvashin:y and rinsing could not remove them and might actually increase the irritation. Several hours of intense ;-tching or other irritation could ensue. Quite3 possibly agents could be found wiich wou'@d penetrate the stratum corneum and go no further, eliminating the danger of overdosage which is such a distinct possiblity when psychotropic agents are used. IV. Other Syste- T,actors One factor to be considered is the relatively For use at cool temperatures, this would either have to be changed to a lower value by sorne means or would have to be heated prior to u;se. Delivery could be made fairly simple2. L7 zed ;:- tainst individuals at close range. the "Icouil be delivered by a simple water pistol type device. For longer ranges, the mixture could be loaded into capsules that woulii break on contact after being thrown or fired from a gun. The person who receives lwould be aware 2 of it. itself has a noticeable odor, which could be masked with per- fumes, bLLt probably not removed., Soon after adrninistration Ilocal reaction-i would appear -- burning, itching, and the like. Finally, subjects would be aware of having ':Deen sprayed or squirted, with a liquid. For these reasons, it is highly douotful 2 could be administered surreptitiously. Ordinarily, when an individual is squirted or sprayed with a liquid, the asual reaction :-s to wipe it off his skin. Since the takes a finite time to penetrate -- several minutes at leaet rnuch of the adminis- tere,i ma--erial would probably be removed well before i2t had any time to penetrate. This is a fairly strong argument agair-st applying @i to exposed skin areas, although wiping m-ay have sorne effect of "rubbing it in" and spreading it. These objections cari be overcome by applying tile to Lb(, clothing. The person receiving this solution an his clothing would be 9 aware of it, but clothing removal would normally be too drastic an evasive rneasure to take, unless the nature of tiie liquid a-id the consequences of non-rern,:Dval were known to the subject. If the liquid were applied to the 16- p.ijiLS (or skirt), clotliing removal would be especiany unlikely, for psycho- lo@ical reasons. wetting the (:IoLliing would be in c.onlact with the slin, possibly for a long enough period of time to allow penetration or partial penetration before the reaction to the burning and itcliing would 'ue strong enough @o motivate clothing. -cmoval. By then, such evasive tactics could be too late. were sprayed on t,-xe clothing,. the genital area would be an ideal target, since the scrotal a,-id -enital skin is likely to he more "Peri-ne;@hle" tL- lthr4n skin in most oth2er areas of the boi@@y. Various psychological factors waald er-ter in here also. Ito the clothing woi@.ld probably not work in situations where the clothing was already wet, as "-y ra-.Ti, by firehoses, etc. This could '-@e a potential countermeasure -- hosing oneself down. Use of rain gear could also 0serve to protect the subjects The probjerns of storage and shelflife could be important; these factors would have to be irivee@tigated for the various incapacitating agents both individually and in conjunction 17- V. Recommencl@itions A. The liscarry" psychotropic or other incapacitants which depend on the bloodstream to carry them to their target organs can, in all probability, be ruled out if quiclt incxpacitation is desired. There is a cha nce that an effective agent could be found which would penetrate the 2 stratlirn cor-ieum - land then go into the bloodstream faster than but 5uch a chance seerns remote. B. should be considered as a possible vehicle for "irnplan- tation" of skin irritants. Studies should be made with various irritants, check- ing for absorption time, duration of action and effectiveness. 2 @comes into active consideration as a -jehicle for skin irritants, several other operational characteristics should be c:eterfnined by- direct investigation. 1. Studies )absorption through different types of clothing should be anidertaken. Various materials-- cotton, leather, synthetics should be checked, as well as the effects of several !a2yers of clothing, loose tightfitting garments, etc. Z. Investigat'-on of the su.@.pected interaction alcohol should be carried out. Also to be considered are possible interac- tions. land other drugs which a subject may hav.- taken prior to or subsequent admiz-iistration. 3. Storage and shelflife 4 and various agents should be inves- tigated. 18-