Special Report Serich, Nu I NATIONAL HEALTH LNSURANCE. MEDICAL RESEARCH COMMITTEE. The (>ausati()n and Prevention of Tri-nitro-toliiene 'T.N.T.) Poisoning. m LOKDOMi rt'Buanm by m» uAjmvr* •TATioKutv oh-iol V ^irvasW* Car jn >-! . C« , 1915-1016. [Cd. 839!).] Price 3Ji., post free 5i. Third .Vnnual Report of the Medical Research Committee, [Cd. miry.] Price (id., post free Id. Special Report Series. No. 1. First Report of the Special Investigation Committee ui)oii the Incidence of Phthisis in relation to Occupations.- The Boot and Shoe Trade. Price 3d., post free 4rf. No. 2. Report of the Special Advisor}' Committee upon Bac- teriological Studies of Cerebro-spinal Fever during the Epidemic of 1915. Price Gd., post free Id. No. 3. Bacteriological Studies in the Pathology and Preventive Control of Cerebro-Spinal Fever among the Forces during 1915 and 1916. Price Is. 6d., post free Is. 8d. No. 4. 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Poisoning. Price Is., post free Is. 2d. No. 12. The Classification and Study of the Anaerobic Bacteria of War Wounds. Price 2s., post free 2s. 2rf. The following is published under the direction of the Medical Research Committee by Messrs. Longmans, Green & Co., 39, Pater- noster Row, London, E.C. 4. Milk and its Hypienic Relations, by Janet E. Ijine-Claypon, M.D.. D.Sc. (Lnnd.) Price 7s. 6d. net. NATIONAL HEALTH LNSLRANCE. MEDICAL RESEARCH CO.M.Ml i FEE The Causation and Prevention of Tri-nitro-toluene (T.N.T.) Poisoninjj;. r-^ //■ Medical Research Committee. {XallounI Health Insurance). The Hon. WALnoRF Astor, M.P. (Chairman). The Right Hon. Christopher Addisox, M.D., M.E*. The Viscount Goschex {Treasurer). C. J. Bond, C.M.G., F.R.C.S. (Hon. Colonel A.M.S.). A. K. Chalmers, M.D., D.P.H. (Lieut. -Colonel R.A.M.C. (T.) ), Professor William Bulloch, M.D., F.R.8. Professor F. G. Hopkins, D.Sc, F.R.S. Colonel Sir William Leisumax, C.B., F.R.S. Professor George R. Murray. M.D., F.K.C.P. (Major R.A.M.C. (T)). W. M. Fletcher, M.D., Sc.D., F.R.S. (Secretary). LNTKOULcniON The enquiriw of wliith Dr. Mixin? givM an account in the prcsfnt Keport onKinattU in a rt'qut*t ma4t> in Auguitt, 1915, to lUv Apj)lii-«l I'hy.-ioiojjy lK|«irtnn-iit of i\\v MfUiral K«-«-arch C'oniiiiittce by the Moliiai lii-iH-ctorn xi<-.>li.gy of trinitrotoluene. In tlie proviinw nionth-s the.se Inspectors, Dr. I>'gge and Dr. Collix, hail their attention laUitl to the occurrence of ^erioull ttyntptonis leading to to.xic jaundice among worker^ engaged in the nianufucture of T.N.T. or in its manipulation for tilling munitioiLS of war. The lirst reconl<-, and from its u.te in a filling factory in August, I'JI5. Kut already in a lilUng factory in .luly. IDIj, a ca-^e of to.xic jaundice had heen rcjiorted. The .^yrnptomH of iMiisoning wen- «i!ioning from the imlustrial use of iutro-cora|H)unds «rts well known to b«' the skin. The rapidly increasing use of T.N.T. at that time inatU- tho i-ition «>ne of grave anxiety, and had it not been for tli.- pre- ventive measures, iuunil on jm-vious knowletlge and cxiHrienco of the nearest analogies, which were then pronjplly adv.xatwl by the Home Otlice, the mortality from ihia |>oisoniiig. wtiich Ivancetl during 1915-1(1 until the autumn of 1016. w hen it i«hcth avenues of entry. The work U-gun in these circumstances under the dirtntion ■ f Dr. MfKtre at the ('ommilt«T"s Appliid Phy.siology I>opart- "lent had for its imnu-diate object the .settlement of this qnnttion f the mod", or nnxles, of entry of the |>oison, with a view to H» . iTectivc prevention. The enquiries of Dr. Mos.sible by the supply of mnloriab for laboratory exjwrnncnt- and by facilities obtaitutl f..r him at the factories by the H>me Ollice. acting with the rc.nly co- • iK'ration of the ivrupiers and of the Mini.stry of Muiutioiw. I .>r the opp wxuut-iJO ion M« Su j c » s «p.st. \i 4037 17 These investigations show how far the measures adopted in the original emergency were corrctl ; it was inevitable that praelice and e.\i)enenee, illuniinated by scientific enquiry, should have called for their niodilicalion and j)rogretii)|miii()l l>y >\ iiiiitoiiiH illiistruting the deficiency in oxygen traasi»ort, and tlie jcjus. (juent oxygen famine, which in intenxiticd in time of mttl, a^ is shown by breat hUtfunettii or nir hunger iij)on exertion. At U-a<*t witliin wifle limits, this condition in one from whirii the body can Mpiiliy recover. If the fn-wh entry of poi.son U« preventttl, what is present in eliminated and the n-d bloo«l coqiUHcles are rajiidly restorwl by reversc-d chemical change and by fresh j)roduction. or bs not kill. The fiital ivsults of T.N.T. isiistiiiing have Ixen due to two other |)atholi)gieal conditions. The most common ha.-t U-en u destriution of liver siilHtance, oven-oming the efforts of the botly towanU re|)air, and the outward sign of this is given by the of bile-pigments from the liver to the general system. These pigments give the yellow tinge in the skin and other tissues to which the name " toxic jaundice " of this disen.se has n-fer- once. The second antl rarer form of fatal ending has \icon the so-called '■ aplastic anicmia," in which the blood forming organs fail in function and a progressive Kkss of the blood elements results. At present ls)th "toxic jaundice" and "aplastic ana>mia " are incurable and rapidly fatjil disea.ses when onco Ostablisheth are concenutl in the maintenance of normal blmxl conditions, and he develojvs tliis line of argument fully iiv his Keport. I'lMin pn-sent evidence, however, it is possible to hold, ond some do hold, that while the cyanosis due to T.X.T. (loisoning i.s that characteristic of ntnny nitro com|)ounds, j-et T.N.T. , or sonic of its isomeric impuriM-^ i r . i .• or other of its ilerivatives in the Ixsly, may have .1 1 upndent variability in the degree of cyano«.is on the one hand ami of jaitmlice on the other. Cyanosis is the inevitable ami invariable rr.sult of TNT imisoning in ex|)erinut»lal animals, while toxic effects uptm the liver have bi>en verj- ran-ly pn dur<»j (ii) ChanneU of ahsurplion into the ImmIu 1 1 (iii) Fate of ahnorbfJ TXT 10 (iv) Aplastic Annnia causing T.S.T. imm.ini.j ... J| II. Hesk.\kk T N.T in tiik Sy.htkm. anu tiik ('<>n- NKtTio.N (.!•• .Minor T.X.T. Ii,i.xk.s.s. Toxic Jain- DUE ANI> .\|'I..VSTIC Ax.tMIA. (i) Action of T.S.T. on the bloo-l 3.1 (ii) Toric effects of T.S T. comjxirrd with thoi,- „f Dinitrophenol 37 (iii) 3/iMor T ST. illness caused by /ftM'x>li.-*iii. 42 3. Toxic jaundice and ftpla«tic anirmia a,s n rmult of incroa««'«l bacmaglobin mcta- ImUsiu. 43 4 ludn-ftiions of incifjvto*! baomof^lobin nw- taboliMU among T.N.T. workerji. 44 S. Powflihility of the dirrrt action of TNT. niMin the liver and red in.'\rrnw. 4J5 (vi) Cases shewing intimate relation betireen Cyanosis and Jaundice ... ... ... ... ... 40 V. PROPnYLAOTio Measures. (i) Early detection of Cyanosis ")4 (ii) Ventilation ... ... ... ... ... ... 54 (iii) Prevention of skin absorption ... ... ... ri4 1. Provision of sliell-filling machinery. ... 54 2. Protective clothing, gloves and boots. ... 55 3. T.N.T. solvents and protective varnishes for the skin 56 (iv) Removal from T.N.T. u-ork of persons specviUy susceptible to the poison... ... ... .. 58 VI. Treatment of Cases 61 VII. Appendices. (A) Effects of xveek-eruls, holidays, and alternation of labour . . . . . . . . . . 64 (B) Analyses of Factory Air for Dust and Fume.s . . 68 (C) Amounts of T.N.T. absorbed under various experimental conditions . . . . . . 71 (D) Experiments on Protection of the Hands. . . . 73 (E) Protocols of Experiments on Administration of T.N.T. and other Nitro-Compounds in Animals . . . . . . . . . . 75 The Causation and Prevention of Tri-Nitro-Toluene (T.N.T.) Poisoning. AN Aivor.vr OF RKSKAKCIIKS HV THE STAFF OF THK AI'l'LlKI) l»HYSIOL()(;V UKl'AKTMI+NT OF TIIK MKDICAL RESKAUCH roMMllTKK. KKPORTKll BY BKN.IAMIN MitoHK, D.S, .. F.R.S., M.U.C.S . L.H.C.P. I. Intkodcctiox. Thi.-* iv{)<>rl i^ iiiteri«lfi!4uning amongst workers manipulating T.N'.'l'. in the footorie»». Tlie work wiki (wirried out for tho first year by the writer, as^iitteil by Mr. T. .\. Webster ; in May, 1910. we were j«)iiUM| by Dr. O. A. \N'von, and tiie pro.sfcutitjn of the work in facttiry and UilM)nitory has oceupieio the thnt- iiilrogroups (NO,) am symmetrically arrangef nitration and purification ; ihert- are aUo small anionnt.H «>f nitruted mcthivnc.s and other sulxNtantx-o. The que^tion of I he n-liitive .shan' of thc>»> vnriouH impurities «<>n- tributinu to the production of the toxic ctTicts on the workem has Ix-tn j^oiu- into fairly fully by our>«lvc!., and i* now U-ing »till furtln r invr.<>tigated by other i>li»', for the pharntaco- logical action of these suKttances |>o?es>ed high enough toxicity to a4-count for the ofleets sr<'n amongst the workers, that workers on pure T.N.T. showtnl all the symptonis. and that similar toxic oflocts rosndtcd in aninirtit treafetl «ith pun> T.N.T. The symmetrical tn nit ni toluene is the main constituent of the high explosive TNT Itccause it is that one formed «lnii ■.• . . ... 10 toliKi(nc fCjH5'''W3> is nitrated fully in the woll-knowii processes with sli-ong nitric acid ; it is assigned the formula : — CH3 ''^2 r= Symmetrical Tri-'nitro-toluene H -''■''■''■ The ]iurc i.rodiict is a hard crystalline powder, the crystals Mhen thrown out from hot alcohol form long glistening needles. When free from impiu'itics it is almost odourless, unless fine dust of it be stirred up to irritate the nasal mucous membrane, and tlie smell of commercial samples of lower grades is almost entirely due to lower products of nitration and other impurities. It melts at 82"C., and sublimes slowly at this temperature. At atmospheric temperatures its vapour pressure is very low, and practically none, as we show below, is contained as vapour in factory air. Tiiis substance was perfectly well known as a high explosive internationally, and was used fairly extensively for mining pui'poses, long before the war. It was not only used alone, but in mixtures with diluents, and the varieties known as " Amatol " are of quite pre-war days. It owed its successful introduction in the times of peace as a blasting powder to two excellent properties of such an explosive, viz. : (1) its high stabiUty, so that it could be relied upon not to go off spontaneously, but remain stable imtil intentionally de- tonated ; and (2) its low toxicity to human beings, so that it did not induce illnesses and poisonings amongst those employed in its manufacture and after manipulation. In sj)ite of all that has hapj)ened since, these two properties it must be admitted to possess in a high degree. As regards stability it may be hammered or turned up in a lathe, and as regards toxicity, any pharmacologist would agree that the toxic and lethal doses showai below are relatively enormous doses. Paradoxical as it may sound, it is these two safe properties which have conduced to the greater ]mrt of the mischief. Used aright they may be made to conduct us to relative safety, both from toxic effects and from fires and explosions ; l)ut, treated as ab.-^olute safeguard*, they may lead to T.N.T. poisoning on the one hand, and to fires followed by explosions on the other. When once it is realised that it is a low-grade chronic poison ^^^th which we have to deal, and the channel of entry to the body is known, and the earliest symptoms of its presence in toxic amount recognised, all the means are then at hand for practically sweeping out T.X.T. poisoning, and that goal we are now rapidly approaching. .11 ANo, wlirn it has heccmp rcccgnifttl. a.-* it Iwim how, how iiiHuiniiinhIc it it once any ignition haH cccurrtd, aril that th»ri-- after the high stability xaffguard tlit^apin-apt, a proper ohjeetive iM Hupphed to meanit fur |irfventiun of accidents, for tlicn relianre on higli ntuhihty is replaeene««.4 w'hieh w»» have itnlici-i.i, iiiu !i,i'<' !,..■ .i-jH'cl of eX)" ; ' of T.X.T previous to the war. Thcexi It is li,w-..| i- w iHlieve, .<>oiind. for w • of ilii a.s well i\s dinitiut'liu 11 -. ! and \]i|i*»ivc.s for the lH|urtniciit Suppl; 'onlirm Pmsscr White thi\t dim'; mort< piunoiioiis than tiinitrutoluenc, iind that both dmiiro- toluene* and trinitn>toluenc are pmcti«iorj)tion of lhes<< nitp' < m. in general, ti.ire nn- -.Mue desultory ol>-.erviiti'>us an- 1 r. in the i>i. VI I r i..rio«l by lM»th our nun . i .i .;.if..t Thus 1 I Min.* iit a pi i . • .-n t)ei cirr Ar (LehiL L - ,acf-ver»ithrrui.^ |>rrcht. o. riofitu* u. O. Kiglcr. L«i|>*>g, \y the kindness of the mana>;ement hen-, we were proviiied with a mean.s of aspirating the air from over the molten T.X.T. in the \uinn, tlm>U(;ii a system for eolkxting •■ fuiue " devi.sed as follows; A larj^e funnel was huiiy mouth downwanl ri)j;ht over the centre of the lar{;e double jiu-ketctl Utiler in which eruur. Thi-* wide . ^uiother Diitxide the hut. and a> the ex|KTiiM. i.ir three weeks round aUiut Christmas, IKl.'i. th. ti.iii-ai.)U frum the hot air in-ide to the <ited on the funnel and IuIk- within*the warm hut. Then- wen- a few delicate cryhtals of T.X.T. in this tuU- at the end of the ex|KTimpnt, hut the main amount (and that, an will \w sc«ii Im>Iow, not very much) was ftiund on the • - ' ,.f the ftuuu-1, on the first gliuss tuU- and in the ^! To make sun- r.f < ..ttip!ing to a g.k» au ter, and fn»m this in s«'rieM to a Hunsen'?' water suction pump. The air WHS ikspiratetl away from ovi-r the molten T.X.T. at a rate of ''lit douhle that at wliich a man would hrrathe. The only thing which condensed in the \J tubes kept at the ii ni|wratun' of carhonie-aciil snow was a few dropt* of .slightly turlijil wat«'r conden.He^l fnim a<|Mcous va|>nur, which were in- jected into a nihliit without any obvious n-nlt The air was then aopirutcil for thre<> w< • > jli the ap|>ivnitus. At the end f»f the exj V. and ammonium nitrate could I-' f'>u'i'l . , in the system. This wa*t thor i wul witji ether, ilic ethcrtal solution drie«l and i: .lied and founil to be alMiut <»-4 grnnune. Hy tin . ,,... ,, ; .kuil a melting jmint determination a j>art of this sulx>ta>tcc w»« shownt to U* T X.T. The n-mainder (Iwing almost the whole nf the o | gramme) wa» then fc«l at one it wiili . .\ny oltM^rAable toMc ciTiTt. a n^ult \i\ keeping' w ' i>»rr\"atioiu« on the dinit eflcet* of foding l' XT i The apparatus had l)ccn working for a period of 40 shifts, drawing air througli at doiililc the rate of human respiration, so that if we wanted to calcuhite tiie amount breatiied bj' a workman during a shift we should have to divide 0-4. grammes, or 400 milligrams, by 80, so obtaining 5 milligrams. The inhalation of this amount can hurt nobody ; it corresponds fairly well with what we later -obtained by even more precise methods of experi- mentation in workshops, both at Factory F. and elsewhere. The first case of poisoning which seemed to be attributable to T.N.T. occurred early in 1915, and in tlie summer of 1915 there was the first fatal case. The reason for believing at this period that " fume " rather than " dust " was the causative agent was that these earlier cases appeared exclusively amongst workers wdth hot molten T.N.T. ; this occupation was not, on the whole, as dusty as other occupations such as filling " exploder bags " or " hand- stemming " with dry jiowder where as yet no cases had appeared. A few months later, however, there occurred the death of a worker filling " exploder bags " with pure dry T.N.T., who had never been near molten T.N.T. Widening our ^^ews someM'hat, we then asked, is this simply another form of inhalation of fumes, or of very fine particles of T.N.T. suspended in the air ? Sureh% in the case of a substance with so. liigh a boiling point as T.N.T. the fumes would soon pass from vapour into fine particles in solid form. So, we set forward on that basis, recommending in factories all possible devices for dust and fume prevention or removal, and on the laboratory side, inventing an apparatus in which, by Imocking and blowing a suspended bag containing T.N.T. powder, an atmosphere containing fine dust could be blown at the head of an animal. Rabbits exposed to tliis treatment for an hour daily for weeks showed no signs of poisoning. It also struck us at this point as pecidiar from the workshop side that in the incorporating and grinding mills of certain factories where the amoimt of dust was enormously greater than elsewhere there had been no severe cases and very little minor illness. Two other disconcerting cases of T.N.T. jamidice, one of them fatal, dropped in upon our train' of thought about this period. One was the case of a wohian who only stencilled shells, it is true in the same room as tamping or stemming was done, but much more remote and less exposed to the dust. The second case was more j^erplexing still, being that of a woman who merely put Avaxed blocks containing T.N.T. 7nade at quite another factory into shells, where there seemed no possi- bility of dust or fume ; later on a second toxic jaundice case occurred on this type of work where only waxed blocks were handled. Parallel to these events many laboratory experiments had Bho\\Ti the low toxicity of T.N.T. administered by the mouth to 15 the mujunty of (>])«-» uf lii>Kir..tury aiiiiiiiil, Ruch a.t nibtiit", guinpa pitfs nnfl wliite rat*. CatH and dopn n?lieve Ittl)oratorv ••.\[K'riinentH, nfU>( prolun^e*! dunitioii, niuxt liere «uf)iie. (So© abo Apjiendix K) 'I'wo rabhitM were eiuh yiviu 1 (;ruinmc (lO<) milli^fmniii) «.f 'r NT. witli their f«MMl iluthj. i\.t|)l Smuhiy-, fnmi (VtoU-r l.'.th (ill DfcemlK-r :JlMt, l'Jl.» ; lM>th <>f tht-w animaU not only nurviviNl, hut tli|M>r1ioiiftle to aii\'tliirit; which an ojx-nitive rould NWiillow at work, iw whowii Ik-Iow, weri- jjiven hy the mouth to u rahhit, whs it |MM.Hih!e, and then only after thrc« or four rapidly re|M-atenic cik.M's ditl w< liver proiiounicd hy the pathol<>ni.-f >ti);ation of the ;ans of thes«> animal.s, a.s well im tlios«< taken froni sevemi «a.se« of human T.N.T. iKii.Honinjf.* The attempt.s arv still liein^; <'or»tinue«l, but it mu«t l>c n-memben-*! in this coimrction what a snjall projKirtion of T.N.T. o|M'nvtive« ever show typical lesions of liver and kiilney so characteristic of fatal |onin(r l>urit»>j the year 11>I«5 the output and manipulations of TNT iiureas*-*! enormously, ami from alMnit .Manh in that year the numU'r of ca.ses U-gan to incn-a^e to reach a maximum in AuKxi-t and S>pt«'mlxr. It was diirini; a visit to a ^mall factor)* II AVf near Ix>nm dr> pure T.X.T.. and a visit !ihowei:. X 4; smell of T.N.T. fumes, no ammonium nitrate, or molten T.N.T. But the hands of the workers were dccpW stained and oily, and a test for tlie presenee of T.N.T. in the urine, a test whieh one of us (T. A. Webster) had just then evolved, indieated the presenee of T.N.T. in their urine. Here, then, were ojieratives working under conditions practically free from dust and fumes, but with hands saturated with oil and T.N.T. Webster's test showed that the T.N.T. was passing into their bodies, and T.N.T. illness had been noted amongst tiiem. (iii) Fate of Absorbed. T.N.T. As AVebster's test indicated the presence of modified T.N.T. in the urine, it formed a most important engine of research for us in our future work, and it is more in this direction than as a diagnostic or prognostic sign that it has its significance. Our attention had been directed from an early period in the research to the fate of absorbed T.N.T. in the l)ody ; we iiad sought for its presence in the organs, faeces and urine of poisoned animals, in the urine of patients suffering from toxic jaundice, and in the organs of persons who died from the poison. With the exception of (1) the organs of Vhite rats which died after taking heroic doses of T.N.T. from acute T.N.T. poisoning, (2) the faeces of rabbits which had received large doses by the n'-outh, (3) the urine of white rats allowed to walk about in the T.N.T. j)owder, Ave had not been able to trace the T.N.T. in the body. . The drug l^ehaves differently in different animals ; if the white rat be given a dose by the mouth, or be allowed to walk about in a box smeared over with T.N.T. dust, the urine shortly thereafter acquires without any treatment tha.t pink colour which is sho^A^l by T.N.T. solutions after treatment with alkaline akoliol. This is the only animal experimented upon by us in whieh the coloi'.r reaction appears in the urine straight away ; the lu-ine in Uiese animals is pink even in the bladder. It is interesting to speculate what the consequence would have been ha.d the human organism behaved like that of these rats, for then the majority of our tens of thousands of T.N.T. workers would be pa sing a bright pink urine. In the ea.se of the rabbit and the human being the colour may be shown in the urine by the procedure presently to be described ; in the cr.t we have failed to obtain it even by this procedure. •Another .'ubstance related to T.N.T. is detectable in their urine, giving qiiite a different colour reaction. This difference maj* perhaps le related to the higher susceptibility of the cat. Webster's Test. Although T.N.T. and also the modifications formed from it in the bodj^ are easily soluble in ether, yet, if the urine containing the excreted compound be sliaken up with ether, and the ether be separated and tested with alkaline alcohol, no colouration results, showing that the ether has failed to remove it. But if the urine be mixed with an equal volume of 20 per cent, hiilphiini- a«nl solution,* tind i. ■ ' • r, the etliiT s<|)iinttt«. Wlu-n ihf amount of T.N.T. in a Miniplo it Iart»f. giving rwo to a MLipition of contaminatiun of tin- urin«" by kiuI.k t with nkin, hair or rlotliing, thf urine whould bt< extnuN-.! lir-' \m(1» t-iher without adiUng any atid ; if a pink rolour tls !i ailding nlkalino al.ohul. it is dui- to T.S.T. uj a.r Hut th.- ii|Hfiinfn III-*"! not Jh* thrown away, th"' lii .tti t-ther without acidifying lia«* n-niovt-*! tho T.S.T. »/ cunUintnntum : nil that is tic<'"..>ary now, to di.icliw**' tlio inoanwto tlio ether, and tost with nUohitlii- iK>ta.«h. l'\.k' t dotail.s and quantiticit for larryii • ^t have ain ly li'H«-t of ihi.s pa[Mr to htato that, ahhoii. •• way uf innkii'g till- test quantitativf i.t known at pn..M;;t. i.\uh ol»*'rv«T ran agnv u|K>n an cinpirii-al ntandani fur himself for judging variou.s ticgrec!* of intcnuity. Having found this t(>>4t for the ]taM«agc of T.N.T. through the Ixidy of tho rabbit, no time was lost in determining whether it applied to human U-ing.s, by obtaining namph-s from T.N.T. worki'pt .-.• vi'.rioMs ffifurit-, iu>d by taking d'».(s of T.N.T. oiin*olvi-s. Korf Mil it. 1\ i; xwis fmind that tin? human Ix-ing abnorlMng TNT ' \n this mtMUfitdfarm, ami na we had at i>ur ili>po-.il I I to our n->earvlM'>«. of whieh wt at on«e pnMev«Ird !■ . i-. IJefor«> taking up the tah* of the.se again, a few wonh« may lie dcv<>t,.d to the rliantf."* whi'h T NT mm«1its«w>« in tho bo.lv I ■ ■ .. I. i.tliir. The < hangcs »*crc »tudit>tl in tin- rabbit's urine, beeaiiso of till dil1i' iiltieti of colU-t-tion of hiinuut urine nt workx and the \iv .1 ••' in the degree to whieh this wa.<« lo«de«l with T.N.T. I ii I l>bit 19 a highly rv^iMtant animal, im> tii.it by feeding on T .N r. Its urine mii U- loadi-*! with TNT. d« rivative anr an.dysis anri idiMtiru-alion. Thi' urines of pra. lu.klly all worker* in T.N.T. eontain thi.* wulk^taiue. but in some th<"re in only a minute tnieo. in othen* an inleiLse ri^nctinn. aiul then' may be a high rvai-tion wherr there is no sign of T.N T " ^ n •.,-•'; •' ■ -• > -, »>f n'action TIlis work has been carried out Ijy Mr. T. A. Webster and Dr. G. A. Wyon — Mr. Webster underlaking the ehemical side, and Dr. Wyon the physiologieal prepaivition and tests on the animals. This work commenced independently ha.s been continued under the super\asion of Dr. H. H. Dale, F.R.S., and Dr. Barger in the Bio-ehemical Department of the Medical Research Committee, at the Lister Institute, and our warmest thanks are due to our colleagues of this department for the special knowledge which they have so freely placed at our disposal. The researches will form the subject of a sjjccial memoir, so the proofs and details of experimentation need not be given here. It may, however, be said that the solution of the problem is now practically complete, and that the interesting changes undergone by T.N.T. in passing through the body are as follows : — The colour obtained when T.N.T. urine is treated as in Webster's test is not due to T.N.T. itself, but to a substance formed from it by the reduction of one of the nitro-groups. This substance is 2:6 dinitro, 4 hydroxj-lamino-toluenc. It is excreted in the urine, conjugated with glycuronic acid, from which it is liberated by the treatment with acid. The fact that the tri-nitro-toluene after the prehminary reduction is finally excreted as an ester of glycuronic acid is of interest because glycuronic acid shares with the sulphonic esters, or the so-called ethereal, sulphates, the task of removing from the body in innocuous form such a large number of poisonous substances. These poisons may either be formed autogenously in the body by physiological or pathological pro- cesses, or obtain admission by some channel from without the body. Examples of the first category are the phenolic compounds such as indol and skatol, which are formed in putrefactive processes in the large intestine. When unpaired they are highly poisonous, but if conjugated with glycuronic acid they are harmlessly excreted as esters, and are found in this condition in the urine. The number of drugs which after adminis- tration are excreted as glycuronates is legion, and one of the chief methods for obtaining glycuronic acid is the daily administration of such drugs to a resistant animal. For example, camphor may be administered for this purpose to rabbits. Amongst drugs which appear conjugated wth glycuronic acid in the urine are cliloral hydrate, phenol, resorcin, syn- thetic febrifuges, menthol, camphor, sandal oil, p-naphthol and morphine. A most interesting example of the formation of a glycuronic ester is that recorded by M. Jaffe {Z. f. physio!. Chewie. Bd. 2, 1878, S. 47), which occurs when ortho-mono-nitro-toluene is administered to dogs. The para- and meta-isomers do not yield such esters, but conjugate with glycocoll and with hippuric acid. In view of the extreme tolerance for tri-nitro-toluene of herbivora, as contrasted with carnivora, it is noteworthy that amongst the large number of substances which are rendered less noxious in the body by conjugation with glycuronic acid, many can only be so united by herbivora, while others can be dealt with in much greater quantities by the herbivora than bj' the carnivora. Man with liis mixed diet stands in an intermediate position. Various diets yield varying amounts of glycuronates or glycuronate esters utilizable for countering these poisons, and it would appear of importance to provide for all workers on toxic nitra-compounds of benzene, phenol or toluene, a diet which will yield a good supply of glycuronates. Such a diet should contain plenty of fresh vegetables and fruit, and be, in fact, arranged on the principles of anti-scorbutic diet. There nwy be a utrtiggle between the p- rif o typr •• >■• > ■■■<' ■ Whi' !. Th.n It is ifn|)<;c iii.i\ bqiatiL cclU. «liiih i>tii..it.. >... .Ml, ,. :,„:., Additmnal weight is given ti> thcno olitt-rvntionii bv the result in a recent i..i|-r t.v I!;Ur(. M It. -J,,,,: Z, if, '. . I!.! (VS, I'.i in wIikIi .1 rabbit-. Ill firt- olli.r , «ij ni'- •' hrM 1 ubK in tl. mriill t thuu ot,- an- 1 tionit ccmjiig.iU- M> .u lu iiaJir lliciu ... rhlni ■ : I lunl ; •' id raMly i.-ul.ktid uiul uU iitilittt. It liiK liit-u JMilntrtl frniu the urinra of rnhhitA oitd n r 1 i > iiiftH tl il \Mili 1" N.T. ; niso from human urino nftrr tl,. .,r,il mlnuiu t; 11 1. .f T.N.T , nr.il fmiu tlio uriiw <>f Mi.rk< r- i:t T.N.T. f.i' I, 11, . It in not prfstnt in the urinr of cnt.-i |Miiy adiiuniotrution of T.N.T. The rrlationship of thcsr two Hrnv.\tivi « to Iho original iri- nitro iuhirn«< Am 'hown l>v tlir foil,- .1 v| formulip : Symmetrical Tii niliotohicnc T.N.T. 2 : 6 Dinitro— 4, hydroxylaminotolucne. Azoxy- compound. CH3 CH3 rN'_n _N HNOH United in urine to another substance not derived from T.N.T. Wlien freed and treated with alkaUne alcohol gives pink colour (Webster's test). Formed synthelic- allv by reduction of T.N.T. A z o X y-c o m p ound 2 : 6 dinitro, 4, azoxy- tolucne formed by con- densation of previous compound by acid or alkali. Gives perman- ent blue with alkaline alcohol. Both urinary derivative and syn- thetic ones give this test. In the free condition the hydroxylamine derivative is not innocuous ; in fact, exijeriments on animals show that it has about treble the toxicity of T.N.T. The action upon T.N.T. in the cat (which, like the dog, is much more susceptible than other species of animal) diilcrs from that in the rabbit and man, where the colour tests would appear to indicate identity of action. No pink colouration is obtained when Webster's test is applied after administration of T.N.T. in cats, but instead a yellow colour. Tlus yellow is only obtained when T.N.T. is given. The substance giving the yellow colour has not yet been isolated, but it is hoped as soon as opjjortunity serves to carry out more experiments on the subject. Taking up again the historical thread of our progress on the workshoji side of the investigation, wc had found that cases of toxic jaundice had now occurred not only amongst \\orkers with molten amatol, but (1) with workers with pure dry T.X.T., (2) with dry amatol, (3) with cold waxed block charges, and (4) finally, amongst pellet -compressors ^\■here both dust and fume in the air were at a minimum. The hands of tliis latter class of workers were oily and deeply stained from coming in contact with pure T.N.T. pellets and pure T.N.T. on the benches, but there was practically no T.N.T. dust in the air, and no smell of T.N.T. fume. Also, the Webster test showed that T.N.T. was passing in varying degrees tlirough the systems of these workers. It was this situation which decided us upon making the prolonged and crucial research at Factory F. wliich, iinally, indicated clearly the share taken by the different channels in admitting T.N.T. to the body. 21 Tho inception und conduct of tluH rei«-iin.h niujit now Ijo dcHcrilxMl, but Ix-fore doing ho, in UKhout the whole of then*- n-«-.in hn known to have ln-OMil to lx« in s|ii,.- ct the [MTplexity intnMluctil by his eontiut with T.N'.T., and al»o by the fact that he hml forn\erly W'vix a painter. HIihmI films were taken, staininl, and examined, when the n>markable fait wiw discovereility in siz«5 of the ref iilT.iirs wa-; at ull showiMl that the eas<« wivs, as indicated by the alxive determinatioits, one of npluMir niurmin* Mad this cMeurreii solely it might have Imh-h doubtful whether it was due t<) T.X.T., but just a week prior to the making of tho blooeen taken by Dr. T .M. \*'\lft,v to .m««» an exactly similar case of a woman «i>rker im T.N'.T. at WatfonI ; then* had hen' also U-en no dear ol>serviition <)f jaundice, then- lm«l certainly l>e«'n nn marLnl jaundice and there was none when we saw her she had In-^-n treati-d for intluenzA ami then for gastritis. The nnn>mia wa* prr>found. the IiUmkI flow on pricking the linger w-n.s scanty and tiiin, not welling up into » dntp, but spreading in a thin dark layer over the akin, Mtd it wa« with diflicultv that films were obtained. 22 These films on cxainiiiatiou gave the same result as in the case of the man above, viz., almost normal conii is (III I lie lilixxl. 1 gidilinos, ii.kUH<-a, luul, cyttii<)-.i-, ami |)allr)r». whKli toul.l 1m n.i*..l la •^•\*f^l . a« - .>ii to 8«-vultrt were avoided \>y prrjuiptly tuniiiij^ ciiw.n ohuu'ing the initial Kyiii|)tuint oil contact with llio |X)iMII|. Ax a nwult o( thcHO contiiuufl oWrvAt ionn in th« fA/>(orv, wo \vir«> able in OitolH-r. 1916, Id •.iijjjii-tt n t teristic of early T.N'.T. jMiisoninj;, Ix-fun- i! and to it-iomnuMid tliat di-tii-tion Hhoiild Im : nigns by ulwcTViTs |witri>llin>{ and ul)»MTvnin i\.- .v..i k-h'j. Thi-rtJ i«, \v«' lH-lifv»', n«»o that these workshop exj>eri- nients and observations h.ivc ItHl to the saving; of life, to tho rwlui'tion of the volume of minor T.N'.T. illne-'S. and so by a saviiij; of labour tliroui;h the di-cri-a-e in the nundn-rs of absenti'«>«, to results of considerable economic vidue. Analyses of the air in the sho|>s combinetwalli>wcd by a worker who did not u.so a respirator, have freeft, flushed anssible oonipulsorv. Sui b n-xult.s flemonstnite the im|M>rtanc(> of medical rr-searrh carried out in the actual workshops, and we an* greatly iiulebtcti to the facilities offered u."* at Favershani. It was in Auj;ust, 1910, while visiting the Amatol Pn's i{iM>ms along with Dr. T. M. I>*gge that this factory nvu-anb was first discu«-cd. I>r. l^egge had brought with him i ^ ' (Sonuan respirator, which is a valval metallic l»ox p usofl by workmen who are employetl whert* then* are jv fun>es or gases in the air The pure inconune air is ' by a long wid»' lublxT tulH* froni the o|M>n nir out.-icle. e.\pired air is >.imply breathed out into the workshop tin mica flap valve, o|»etiing outwnrtLt. It was a ipte>tiot\ whether on aerount of their irkMimencM fropj weight and tuljo altachmcnto thrae rMpirat"*-" '■' '— worn AS A daily routine by working girin for m * .Mmixt siniiLir cHctts. » the rxpl<«ivr diniti to m.\nv clf'nth-s. »rr rrcordr»l t>v French ob—rvrr^ shift, but it was thought feasible that we might get a selected number of the girls to wear them for some days, while daily analyses were made of the urine by Webster's test in order to determine how much T.N.T. was really tr.ken up by the mouth and nose. It was pointed out by the writer that the amount of T.N.T. dust in the air at the level of the workers' mouths was very small, as it all fell floorward from the level of the machine moulds, so that while there was plenty of dust (at this period) on floor, benches, and the girls' dresses, very little dust settled on ledges above their heads. These ledges, we were assured, had not been dusted for some time. This contention as to the small amount of dust in the air was not admitted by others present, who appealed to the bitter taste in the mouth and the irritation of the nostrils. It was accordingly determined to make analyses of the air for dust and fumes at the level of the workers' mouths with the results shown below. The process employed in this factory consists in compressing the T.N.T. powder into Large pellets. Two girls work at each machine, one measuring or weigliing with ordinary scales,the charge of powder taken from a box-full alongside, and tipping it into the mould, the other girl manipulates the macliine, takes the moidded pellet, which has alwaj's some loose dust about it, out of the mould with her hand and places it in a box. The Avi-iter asked several girls to remove the cotton gloves with which they were supplied, and found the powder inside caked in the creases of the skin in many cases, and quite wet from perspiration. The skin of the hand was in many cases soft, and the skins of all the hands were a deep orange colour. It was evident that the gloves were perfectly useless as a means of keeping the powder oif the skin ; indeed, on the contrary that they were i)robably harmful in making the skin soft and moist, and holding the powder to it like a poultice cloth. Our suspicions of the dust and fume theoi-y had already been aroused, and the importance of the skin channel presented to our minds at our visit to H.W.C. (page 15) a few weeks previously ; here seemed to be more evidence pointing in the same direction. It was determined therefore that wliile one set of girls were protected as completely as possible from dust and fume swallowing or inhalation by respirators, and not otherwnse intei-fered with ; another set, or some of ourselves, should take the risk of dis- pensing entirely M'ith respirators so that we swallowed as much as was avciilable of dust and fume while actually working, but should have our hands protected as completely as possible with rubber gloves, and other means, to keep the T.N.T. off this most important part of the skin where the powder is rubbed in during the process of labour. The Webster test of the urine was to be made as quantitatively as possible for the two sets of workers — so that a good idea might 35 be i;.itluTc(l iir)t ((Illy of whether the |>oiiiuii entered \ty one or both of thrsf iIuuimi-Im, but ali»o Honie cMtiinatton might emerge &« to their n-liitive im()ortanci*. Dr. Ix'KKe ttpi>rottchetl the clirectonvte of the factory, who rfji'lily uraiitiHl |Hwion for the n-Hfanh to \» carried out ; not only ho, but tlwV pliMt-d a nniall wi-ll rquipiKtl laboratory in the ;;roun(U mljiif<-iit to flu- fintory ontin-ly at uiir ilixito-al ivMil iiicurml a con.'^iilorablc f.x|H-ni «tlicr inattriaU for our um*'. TIm' thi'ii nianaow«t to facilitate the uih-ii air out-sich' near the r«)of. Similar tulx's were al'^ii arranued to be connected uutitidu to an ehi-tric vacuum air pump and iiisidu to an abMorbiin; a|>paratus for catching T.X.T. du>»•• Hucki-*! When makini; an ex[Mrimcnt the ii' ' ' ' at the level of tlic n..-,c and mouth «.i to the machine, uit in tlic ;ur N') ii. •!•■ . I' NT. is used in or near llie-e sheds, but scveml fatal cases i.f T.X.T. [Mii.soiiin)^ have occurn:i "f SepfemlK-r '>th, but had to take them off on ^ ii. 7th and sth <»n account of sore faces causi><| i.<. in- of tlu" riil>lx-r pads. Advantage was takeit of thi.-' mitrini -ion to establish the iiilcti-ity of the urinary reaction when no respirators were worn as followH : — \' McC. Tuesday, Soptomlirr .ith ... R. 2 Thursilav. .'^•■ptembrr 7th ... H. 4 \. F. Tue««lav". ^ i. ... K. 2 Thiintchiy. - U ... R. » The lower pcii..., ,n l,.i': r in the wwl. . ;.- to the partiid •' week end. During our ■ v F. holh on diffrrvnt wr«k-4>nds and a munition \\.>n,' n . i y^ OS we could, first wli-n or immetliatcly after tic -t t>efort> they retunietl un M'li'l.ns ,.r .>f th'> enl of flir (,>iir i\.\W 2G holiday. There was in the average a decided drop in the intensity of the reaction, some urines almost completely cleared, but manj' still showed a good deal of the T.N.T. derivative on the Monday morning. (See Appendix A for details.) Tlie two girls above-mentioned resumed wearing the respirators on Saturday, Se))ten'iber 9th, their faces having healed with the rest, and tiiey wore them constantly while at work until Friday, September loth, thus making a complete week. They could not stand the respirators any longer, on account of the skin irritation and discomfort. The results of the urinary reactions were as follows :■ — V. McC. Saturday, September 9th R. 4 Wednesday, September 13th ; Thursday, September 14th ; and Friday, Sep- tember 15th R. intense each time L F. Saturday, September 9th R. 3 Wednesday, September 13th ; Thursday, September 14th ; and Friday, Sep- tember 15th R. intense each time It is thus seen that in the three later days of the week of ■^'earing the respirator the reaction for T.N.T. in the urines of these two girls was " intense," and as no visible effect on the urine had been obtained and the respirators were making the girls' faces sore, the experiment was discontinued. Experiment 2 in Shop No. 2. Four girls wore respirators, of whom two left the works in the course of the experiment. This v^as compensated for by the behaviour of one of the other two girls, E. S., Mho wore her respirator well and uncomplain- ingly for nearly a fortnight. This girl did all in her power to help us, being interested in the work, and she later helped us in the complementary experiment with her hands protected from contact (see below). (1) L. G. Started wearing respirator Tuesday. September 5th, and wore it till September Sth. Urinary reactions : September 7th, R. intense ; September Sth, R. intense. Left works. (2) S. T. Started wearing respirator Tuesday, September Sth, and wore it from Tuesday, Septcmlter 5th, till Saturday, September 9th, then again the next week on Monday and Tuesday, when she also left works. Urinary reactions : Tuesday, Sep- tember 5th, R. 3 ; Thursday, September 7th, R. intense ; Saturday, September 9th, R. intense. (3) R. A. Wore respirator from Tuesday, September 5th, till Saturday, September 9th, and again in following week from Mondaj% September 11th, till Saturday, September 16th ; but it was more irksome to her than to next subject (E. S.), and she occasionally took it off. The greater jjart of the period, however, she wore it. Urinary reactions : Tuesday, 27 September Sth, R. 3 ; Satimlay. S«-|it.iiili.r 0th It 4, 1 September 12th, K. 3. Xo hitt-r HiKtiniiMi-* ubtaiiiitblc. (4) E. S. Started wcArin<< renpinitor on Tuc»tlny, - ber Tith, wuru it cotuttuntly uiui wi*ll nncr HUh inclu.Hivf, !• \ifis than a fortiiinht of working jK-riodM. rrin i Tueftday. ScptiMuljiT .'»th, It. 3 ; 'rhunMlay, .""n-pteiub i 7.ii, It J . Friday, Soptendn-r Hth. U. 4; TuoHtlay. SfptfiidK-r ll'th. K 4. No lattT Humpli* ol)tainabU'. (Contnist thivHc with rt-iults of »km protection in thin name girl as given Ik'Iow.) Ah there was no diminution in the reiiotiou and tho girl'n face was Ijeinj; ma lo sore by tho respirator pati, tho experiment was discontinued. TluTo is tlius no evidence that in any of thcM.* girU tlieru was any decrejisc in the amount of altertxl T.X.T. Ix'ing excri'tetl an the result of wiarinj; the nuist complete re«pinktory prutfotion that couM Ik' ^ugj;.Ht.'d. (iii) KxperiiiunU on Absorption by (he Skin alone, other channels being purposely txclwletl. The aUjvo ex{>«"rimenls haviti^ shown of how HmoU im|M>rtaneo atksorption fron» the air liy swallowing or breathin.; ••' " i .. i.. nary workshop ronditioiiM, wo r wori. diLst or fuiue. After shiiwint; l.\ tl\. ;•;!! I'iiMi ..f tir ;!; iv tt>8t that our systems wen' fn>e fn>m TNT., we either rubbil T.N.T. into the ]mlms of our hamU (much as a girl would Ix' expoAfil to T.N.T. eontaot in haiulling pcUeta) or else dusted it into our soekA. Exju-rimrnU I aivl 2 mulr on II. M. After p " u visitini? the worksho|M for a d.»y the urine was te^. I only tlie fainfi'>.f trace of TNT i .■. 'ion. W :: Ab<.d T.N.T. into the |vilms of his h ilnnit in thoh uvl* .^n amatol pellet rontainiuk; 2<> [" : i NT. After two h'Mir* A sinn-imen «>f urine WiH |wssr»l. ami this siiowtHl n was (juite a stn>n>; nwtion, lyina in intensity about at tho average given by the urine of the shop worker. The rtd)bing in of the amatol on the previous day had U-en kept up inter- mittently for about six hour>*. after which the hand* were wished with soap and >Tater. The T.N.T. Fraction remnined in grvluivlly 28 decreasing intensity for a period of ten days, after which the urine became clear, althougli 13. M. neither rubbed T.N.T. in again, nor went near any Hource of dust or fume. Tiie first morning after ru))hing in, 13. ]M. awoke with all the symptoms of a minor attack of T.N.T. illness. He had a marked frontal headache, a feeling of nausea, and intermittent abdominal pain. This abated towards evening, but a feeling of malaise and drowsiness persisted for about two days. After a fortnight, and when iiis urine had become free of T.N.T. reaction, B. M. repeated the experiment with the same results as above. Experiments 3 and i on G. A. W. and T. A. W. Dr. Wyon and Mr. Webster then dusted T.N.T. powder into their socks and worked during the day in the laboratory, but quite away (at least 100 yards) from all dust or fume. The result was that each obtained a distinct but slight trace in the uruae, which previously to the experiment had been quite clear. The amount, however, was nothing approaching that in the case of B. ]\I. These t-\vo observers then rubbed T.N.T. into the hands with similar results, namely, a slight trace in the urine. Urinary Reactions.— T. A. W. : September loth, 1916, hands rubbed -n-ith amatol (20 per cent. T.N.T.) in lanolin ; two hours later, R. a trace. September 19th, similar experiment ; urine after three hours, R. a trace ; next morning, nil. October 5th, both socks sprinkled with amatol at 9.30 a.m. ; urine at 10.30 a.m., R. nil ; at 12.45 p.m., R. nil ; at 3 p.m., faint trace ; at C p.m., trace; next morning at 11 a.m., trace. G. A. W. : September 25th, hands rubbed with T.N.T. in lanohn at 1 p.m., washed at 1.30 p.m., T.N.T. rubbed in again at 3.30 p.m., and rubber gloves worn ; urine at 11 a.m. (control), nil ; at 4.30 p.m., trace ; next morning at 10 a.m., nil. October 5th, amatol sprinkled in left sock at 9.30 a.m. ; urine at 10.20 a.m., nil ; at 12.45 p.m., nil ; at 5.30 p.m., faint trace. This varying absorption by the skin is important from the light it casts on individual idiosyncracy. It becomes obvious that some individuals let the poison through the skin with ease, while others by the natm-e of their skin bar its entry, so that on the same job the system of one would be fully exposed to the poison, while the system of the other might be comparatively free. Again, the long delay in the clearing up of the urinary reaction showed that the susceptible person ■^^'hose skin liad become loaded with the poison might continue under the influence of the tlrug for days after his apparent removal from it by absence froni work, owing to the gradual unloading of the reservoir of T.N.T. in the layers of his ejiidermis. 'J'liis conclusion casts light on the increase of symptoms, even in cases that recover, often seen for some days after retnoval from outward contact mth T.N.T. Tho {Mxition no longer ro«ts upon the i-vidt-nco of our own thi\-<- cas<4 ninno ; it linit MJnce lx>en ttttuljliHlutl by tfitU) upplioil to niimy |M-oplf, hw^\\ hh laboratory worki-rH m«ver befon? ex- po-nl to TNT. iiiliiiliktion, uad to onfoniin); T.XT. workt-rn bffori' any ixpi»»uri-. Th«' tochniijuo uwcmI for the ilrttction of tlu- T.X.T. dcrivativo in tlir< urine Iwi^ lK«cn worki-d out on quiuititative lines by iili-< is preM^nte<| liere to round off thi.-* Meelioii <>n variablf ab-iii|itiiin from skin alone. The latrr < \|M'rinientH hhowed that B. M. gives a aln) of one h.ind, while (!. A. \V. xhowj* no r«'U<-tion after rubbing llH) niilli},'nuns «iver hand and forearm. It ih interesting that (J. A. \V. j^'etrt a dermatitis while U. M. gels none. The fiut that (J. A. W. thnvs not give the n-aetion froni oven l<)0 tnilligram.H i.s not riment was carrii^l out <»n nine lal. : persons (ineluding H. M. and C A. W.) ; of these H. M only one fo givi- a |¥>sitive n-sult with 10 milligntm.s ; |. : lalM)rator>- lioys. L. I,. B. ami L. \V. ('.. gave |)o.sitive n*-sult.-. \uth 20 milligrams. The T.X.T. in all the.se easett \va» applie«l to the {Mvlm in 1 |H>r rent, .solution in aeetone. A large se.ile ex|)criment is now In-ing made u|Kin all on- coming workerx at a eertain mtmition wnrk?> In the conr«^ of this many men ami women ha\ ' ' '•> an- here given to pn)ve the • - high variability by the eonsid. .Mm i>|i' I I MS having 10 millitir.tm.- tit .t(«ti>ite apphol tt> thr p.ilm -lnu •! in 33 ea.s**!« only 3 per cent, of poiitive result, i.«-.. :i2 M«ie II. j^.itive, I jtositive. When the dcvv on the jK»lm was inereanod to l.'» milligntm.s, out of Mil men tcjitod 27 (23 per cent.) were positive ami 02 (77 |ier rent.) negative. When women o|x>rative,s were tt'sted similarly with 7 milligr.imis out of 107 cooes lo (U [kt cent.) »Tre poRilivc and D2 (JUi per cent.) 30 negative. On increasing the dose to 10 milligrams, out of 65 cases ]ii (29 per cent.) were positive and 40 (71 per cent.) negative. (iv) Experiments on the Effects of Skin Protection in Diminishing Absorption. Experiment I. The greatest difificulty ■\\'as experienced in keeping the hands of factory operatives clear and free from contact with T.N.T., on account of holes in gloves, T.N.T. dust getting under gloves, and, in intervals of work, operatives remov- ing gloves, or touching contaminated surfaces Ijefore putting on gloves. There was no disposition to thwart our work, we ex- perienced great patience on the part- of most employees, but the problem was like that of teaching the principles and practice of asejjtic surgery to a lay person without technical knowledge, or any considerable education, in a week or two of time. We only succeeded in keeping the hands chemically clean for over a week in one girl, E. S., who had previously helped us so well in the respirator experiment. Tiiis we could only manage by asldng her to come to onr laboratory when goiug on or coming off from each working period, so that we could test her hands with alkaline alcohol to make certain T.N.T. had not penetrated to the skin, and b}' putting on and taldng off the preventive coverings ourselves and thus making certain this was done without any contamination. After several failures, -u'c finally achieved our object by putting next the sldn of the hands a pair of rubber gloves, then bandaging vdih. an ordinary three-inch surgical bandage over the top of the rubber glove so that no powder could fall in between glove and hand. The bandage reached from -nTist to elbow, and i:)rotected MTist and forearm. In order to preserve the rubber glove from mechanical injury, an ordinary pair of cotton gloves, such as are supplied in the workshops, was worn on top of the rubber gloves. The girl was quite able to work in tliis outfit as no delicate finger manipulation is required in the process. For nearly a foi-tnight, from October 10th till October 23rd, 1916, inclusive, we were able to keep her hands continually clean as shown by the alkaline alcohol test. The reactions of the urine \Alien she was wearing a respirator have been given above. In the period with no respirator or the shop respirator only, and with hands unprotected or partially protected in various ways, her urinary reaction had varied between 2's and 4's, that is about the shop average, as follows :-^ Urinary reactions period previous to hand protection : September 22nd, 1916, R. 4 ; September 25th, R. 2 ; September 27th, R. 4 ; October 2nd (Monday before ivork), R. faint trace ; October 5th (morning), R. 3, (night), R. 2 ; October 6th (Friday morning), R. 3 ; October 9th (Monday morning), R. trace. Ii was on Tuesday, October lOtli, 1916, that we first managed to gei her hands free at the end -of a shift, and this was maintained until Turxl.iy. •fctobtT 24th, wh«-ii they became fouled throuKh a hole u|)|M-uriiit( in a ruhlx-r j^love. The uriri.m hmh,^ (.,r this interval with (-li*aii lianiU Hen- UM ftillouH : 'I'i, ix-r I2lh. K. tnice ; Friday. (KtoUr 13th. K. I ; S.i -r Nth, K. trace, Thur«-lay. (Xt..lnT lUth, K i. - i .i.i.iv. ().t..lM r 2inh. H. I ; .Siitunlay. (ktolxr -M«t. K 1 , M..nM-r ^ti)Ve<> iiml haniU t-ttntuniinattti ). This ex|X'rinietit ur|M>>i<-ly NU'allou-in>{ the amomit of T.N.T. indic'ateriment in which we should work oursi'lves in the workshop u[M)n the wime task. Acconlinnlv, the writer (B. M.) ami a voluntary co-worker. Miss M. ti. Francis (M. (J. F.) worked for a we«'k on one of the sanu- machines o|M-rale4l by the factory employees and luuler similar conilitions in the sjinie «hop. All pn)ttHtion to mouth and nose was dis|>ense«l with, but tho hands were thoroughly protect*-*! by leather jjlovc- next the skin anil nililK-r (jloves outside of tlu-se. At th<' t«'nnination of each working; |M'riiMl. a negative n>sult was obt;h wiml on two of the days of the ex|Mocket handken-hiefs. Yet neither of thrin with hariils no pnitecteti showeeri- ment in the following week, when it w ;« fl. « i-nrd that the two »\orkcrs .should o|Hn»te in re^pinM' ihe hands un- pnitcctr.l Unfortunately a fire, followed by an explosion, wrecked tiie workshoj) in which the experiment was to have been perforined, and the experimenters only escaped being involved by a detention in London on business connected with T.N.T. poisoning. This portion of the experiment was subsequently carried out by B. M. and G. A. W. at an exploder bag filling factory B., and as it is the proper corollary to the above experiment it may be placed here. Experiment 3 at an exjdoder bag factory B. On June 4th, 1917, the two experimenters, G. A. W. and B. M., spent a whole period of working in the factory, close to the actual workers, so that they would take in (by breathing and swallowing) the same amount of dust and fume in the air as the workers take in by these channels. They did no work on machines during tlus period, and protected themselves from all contact, save that of inhalation by mouth and nose, but in this latter respect they were as much exposed tis ;iny (ipciai ives. On the following day the ]ii( caul ions against skin absorption were set aside, and the two cxpiiimenters proceeded, -with bare hands, to manipulate the macliines and behaved like ordinary workers. The results given below show the contrast, in these two days of a workshop experiment, between a worker exposed to all inhala- tion of dust and fumes and a worker exposed in addition to actual skin contact with the deleterious substance. They show also the difference in degree of absorptive power of two different workers. Urinary reaction at end of shift. June 4th. Idling in workshop with liands protected. G. A. W., very faint trace. B. BI., faint trace. June 5th. Working maclunes with hands exposed. G. A. W., R. 1. B. M., R. 3. This experiment accordingly confirms the results of the rubbing- in experiment and of experimental exposure to the acetone solu- tion of T.N.T. (see above). (v) Determination of the Actual Amount of T.N.T. in the Air of the Workshop and Estimation of the Maximum Amount which could be Breathed by a Worker during a Shift. A prolonged experiment of this kind had already been made elsewhere, but without any attempt at exact quantitative accuracy. No elaborate aj^paratus was at our disposal, so we utilised as interceptors two large "y-shaped calcium cliloride drjing tubes fitted with rubber connections in series. Electric connections were taken to a vacuum pump, which was placed in the open air to avoid all daiiger from sparking. The mouth of the al)ttorl)iii(; \J tulje won |jtiu.-ctt.«eil tn scries through thr two \J IuIk-., llitti to ii Kiis meter lihuwiii^ litn-H. nml h<-iue to the vuc-uuiii jjuniji The pump wa** run itpproximately at inti-rvuU of twfiity miiititii on iin. anil thii v\.k-> continued for n whole shift |>i'noH-en Htop|M-d. On letting with alkaline aleohoi at tho em! of the e.x|M'rimi-nt thit tiilM* ^ave no pink eoiour, thu« showing that ;ill TXT. hiul Uen al>HorlK'y the tir-t \J tulu-. The water in the first tulw shouetl tloatinj; in it a numt>er of |>artiele-< of iiiHohilile |Miwder. hut the aniouiit was s«'f thn-e e.x|K'riiiic-iitH (jivi- II miiliumniH, equivalent to DIHtrnkin, or a pinV heariment in the shop, with their hamls pmteiteil as ih^seriUtl alnive. While tiny work'tl in the shop, (J. A. W. and T. A. \V., n-frainiiiK otherwi.M- fn)m woim; anywhere 4i«ar MOiiri'e* of T.X.T. al>sorpti«Mi. nd-' .loses ,,f T.X.T.. <;. A. \V. tnkinK I T. A. VV. took !«• milligmms daily, an, level whirli the air analysis •thow«>d niif^ht )»' t: air The urinary reactions ohtained ran -w tlir ohlaimd hy B. M. and M. (;, F. in th and eteanni^ oveniiifht. IVIails are wa]!MU..i :oid ii.li.d..!^ u.l t!w .,.r,^l,r.| ,|, (ni>t-rBl'M) •' nselve. whil. ..1 the J. in'tn faetory l.NeUa* tho^e / to I or 1 * . iiili* (' ff»r 34 Moreover, it is clearly shown that this is only a small fraction of the amount taken up by the average shop worker, and there is complete nightly clearance. The above experiments taken in their entirety appear to us to afford concordant evidence not only that T.N.T. is absorbed by the skin, but that under ordinary average workshop conditions this is by far the most important channel. Observations were made at Factory F. indicating the close connection bgtween minor T.N.T. illness and toxic jaundice or aplastic aiifemia. In order to avoid splitting up the clinical evidence this portion will be reserved till after the next section dealing with a research at a National Shell Filling Factory. III. Researches at a National Shell Filling Factory (A). These incpiiries were carried out in November, 1916, and the particular factory selected was chosen because it was one of two national factories which showed at that period the highest incidence, both in minor T.N.T. illness and in notified cases of toxic jaundice and deaths from toxic jaundice. It has since turned into one of the healthiest in the country, and a member of its medical staff recently informed the writer that he attributed tliis happy result to the early detection of cases by a medical officer patrolling the workshop. The other two changes which have been made, as we have been informed by several visitors to this factory, are that all the processes arer carried out with greater cleanliness, and, secondlj', that increased forced ventilation has been introduced. The analysis of the air of one of the chief workshops of this factory where most of the cases of toxic jaundice and fatalities had occurred shows how very little T.N.T. dust or fume was present (see Appendix B), so that, in our opinion, this cannot be an important factor in the change for the better. The results obtained here formed confirmations and extensions of our earlier work ; they have already been given in another report, and so need only be epitomised here. (1) It was sho\TO that because enough stress had not been laid on the danger of skin absorption sufficient attention was not being paid to keeping all processes clean. As a result, persons engaged in cleaning up the soiled shells with oily rags were often cj'anosed, and amongst such persons then classified in this factory as " shell finishers " there hafl been several cases of toxic jaundice. (2) That the chipping off and rubbing with oil did not com- pletely remove T.N.T. from the outside of the shells, so that these went on to the so-called " clean shell store " covered by a film of oily T.N.T. This accounted for the presence of T.N.T. cyanosis and iUness in the " clean shell store," and for the occurrence of cases of dermatitis here. This and the fact that railway men loading filled shells on to railway trucks had been cyanosed or jaundiced showed again the importance of skin absorption. (3| .si.iliitici wiTf i)lji;iiiiiil III tlif vurioiit MCftiiiim mIihIi showed clciirly the ijreat iiiii»ortiiin.e i»f minor T.X T. ilhii-«i» la oauriiii^' ^K'kia-Hs and aUH*uti>tMrtiu. The iueositi<>n at whii-h the molten amatol wiw |)ound. Till- w.is rontirme<| by our analysis of the air during lliin 8ami- "hift, iiur estimation^ yiehling only M milligrams, or li's.t than one-tenth nf a gniin, a.s the available amount jkt worker |kt shift. The greater part even f con- gealed amatol at least half an inch thi<-k all round the |>ouhng places, sora|K-d it away with metal -.eriiK-rs, and swept it up dry. Our analysi'H also demonstntted that there wen- pnuti«l to skin contact annnk|(k .vm> .\i'I a'H-k An.»:mi\ (1) Artinn of T..\T. on ihf «/o<«/. Tri-nitro. toluene iM'longNto a very large cUi.s.s of IxHlit^.includuig both the organic nitro <-om|M)unds and their re»s.ses., the comnxui i-haracteri-tn of acting in the lir^t wt-'am-e on the IiIcmmI. This iKtion is Ivt-wsl on a rhiiiiire in l' ' ' '!■ h is to a \ . ronvertebin and nu ■ Sin< e tlie«e hn'ni" .iuii>t fun.' . ur,r- ,• f-.llow-. llu: h I r :ii ha-" \m-VI\ i\]' ■!■ '• ■ ' ■■|'<-j»rs, more • • . , , _ . . i" i i Tlu.s i.s ihtf stAge tti niiniir T.N.i. diiirw, v»r)-tng 'lom VMC to CMC orronting to the dcgroc of deficiency 3« Tlic symptoms complained of by the pcatients are very similar to those of niountaiii sickness, such as breathlessness, tightening in throat and cliest and difficulty in breathing, giddines8,'tlro\vsi- ness, nausea, abdominal pains, general malaise, appetite at first stimulated, then lost. The changes in appearance observed before any jaundice occurs are also due to the changes in the blood. A drop of blood obtained by pricking shows a venous blue colour which does not soon turn scarlet when exposed to the air or when absorbed by blotting pajjer ; this effect is quite characteristic and might be used for diagnostic purposes. This alteration in the colour of the blood shows itself by producing ashen-blue lips, and also in many cases by giving a peculiar pallor to the face which simulates antemia but is not anscmia, for counts of red blood cells and estimations of haemo- globin give normal figures in these cases of minor T.N.T. illness. Although there is a normal number of red blood cells and a normal haemoglobin index there is considerably increased labour thrown upon the hsematopoietic organs due to the increased rate of breaking up of the altered red blood cells and the increased rate of production of hfematocj'tes, balancing this loss, with an overworking of the red marrow hsematoblasts. Similar effects occur in malaria and in various forms of jaundice. Evidence of such destruction and regeneration is afforded by the very frequent statement volunteered bj' these patients that their urine turns dark-coloured during an attack, and by the frequent presence of bile-stained serum. The relative degree and incidence of this cyanosis and its attendant symptoms differs Auth the different organic nitro- compounds and also in the case of the same nitro-compound according to the species of animal to which it is administered. So also does the frequency with which these minor symptoms lead on into toxic jaundice differ in different animals and with different drugs of this class. These facts are in interesting keeping M'ith the results obtained industrially upon human beings .Avith other nitro-compounds than T.N.T. which are more directly poisonous when absorbed, such as dinitrobenzene and diiiilro phenol. These drugs would appear in man to cause death Ijcfore the toxic jaundice and the tyjiical liver lesions have had time to develop, as does T.N.T. itself in the case of the cat, to which animal it is more toxic. A case of toxic jaundice \vas, however, reported some years ago due to dinitrobenzene, and it is here to be remembered that T.N.T. before its present enormous production had the most innocent reputation of any of the group. It may be added that when given in large doses T.N.T. also kills without any jaundice or liver lesions in all the tj'pes of animals subjected to experiment, viz., white rats, guinea pigs, rabbits and cats. :«7 Tlie li-ioiu^ 111 liviT uml l)oi>t< iiiarnKs in t)ifHc- ^Jx•cit•s of luiiiiiuU not »|»i-i lullv aa li Itttir and more or Icm ihrwim ■ _ cliangc)>. (li) Tuxic EfftcU uj T.S.T. cumpureU unlh thuat of hnntruyhtmA. Till' i-tIi-<'tM of (linitn>|tiirniil, whitli hiw nt Im-<-ii htitird alxive. Over a year a^'o we inve!h('nol amongst a iiuiuImt of other nitro coni|iouniiM at the n'<|iie-( of lin' Departinent of Kxplo^ive?* Supply, ami re|)orteoratury aniniaU tlian th-nitro-tolueiiu or any of the other Kuhtitances Hiibiiiittey a n'[K»rt on " Inf^xi^wHon by Dinitniphenol,' hy Professor Ktiiinie .Martin. >! cle I' classe, and his <-ollea;;iie« m IV.iiice* This siit) to Im- iiuieh nion- dan^jiroii- to the workers tli.u t-oiisideralile miiiilMr have died fnun its tdleots, and ju L .1- ..ilh T.N.T. a much larjrer nuinlxr have suflerfil minor poJHoning and Im-^'ii imapa-spn(Mi. with a feeling n| tightnrM (rct{uent .itt.i> ks have Ijccn giutro intc-stinal, ] .>!>• (uirnl ' anorexia. vi>mittn(; and >oroctinir» »light |.iui>isonoini and kills liefurv liver lesions have ha4| time to apjK-ar. The Freiuh oli^ervers state tl»at thcsiv fiicts ralhrr point to altsoq.iioii of the |s»i.son throtiph the pulmonary ntid di»»>«five ii ; I-, but they do not app«>ar to have mae ex|K>seil heavily to >1 They maku tin statoiiient. ' I-i>tl'. :;; iio ro^e of all the Workers one mux! • Chir lhank.1 are Awn t.i 1>t I (uiniAtion rited. 38 of absorption of diiiitrophcnol by the skin of tlie bunds and fore- arms." It would appear from tliis, ai\d especially if dinitrophenol is to be introduced upon any large scale in this country, that quantitative experiments ought to be instituted as to the amount of dinitrophenol in the air under ordinary workshop conditions and tlie amount taken up by the skin.* Lal)oratory experiments are now being made by us upon animals and ourselves as to the channels of absorption, and if these show us that skin absorption occurs the problems of pro- phylaxis would be identical with those already u.sed for T.N.T. (See Appendix E.) It is interesting to note, in view of what we have found in the case of tri-nitro-toluene, that dmitrophenol is also reduced in pas- sage through the body to a mixture of mono- and diamino-phenols, which give distinctive colour reactions. The reduction appears to occur in the liver. There are no microscopic lesions in any of the organs, possibly for the cause assigned above. (iii) Minor T.N.T. Illness caused by Blood Change. Returning to the consideration of the minor T.N.T. illness caused by the initial blood change it may be pointed out that, although this is termed " minor," it is probably of " major " importance from the point of view of national economics. In the earlier period of our researches there were at several filling factories hundreds of workers '" off work " and on com- pensation pay owing to " minor " T.N.T. illnesses. All over the country there must at this period have been some thousands of workers temporarily incapacitated, and the economic loss in labour and money must have been very large. In addition this large tide of minor illness was giving the T.N.T. occupations a bad name and cutting short the supjjlies of labour. Now as a result of cleanliness of labour and of early detection of susceptibles and sending them oE to other work, this evil has been combated, and the number of workers " off work " from minor T.N.T. illness has largely abated. * A remarkably interesting observation of the French researchers appears to show that dinitrophenol both goes in and comes out by the skin. " When a worker is going to be affected by dinitrophenol the parts of the skin protected by the clothing, such as are not likely to be stained by dinitrophenol (the chest, shoulders, back and upper arm) assume a patchy yellow colour. It appears to be an excretion of sweat containing dinitrophenol. On the other hand, workers who are unsus- ceptible show the staining only in the uncovered parts, such as the head and hands. This symptom is of importance, as it shows that tlie sweating comes on when the organism is impregnated with dinitrophenol ; it is an indication for suspension and treatment." Many T.N.T. workers have assured us that they sweat pink sweat under the armpits, where there would be little chance of direct contact with T.N.T. dust. 31* (iv) Action of Fare T.S.T. and of Jinpuntus It hiiM U-fii often diwu.*Jtfmia by it«)me otiicr uukiioMii .•.ub^tiwue. It i.-* excec«lin>rly dinicult to pn>vidc a riponius pnx'f • whole of thew effi< t.s are due to tri-nitni-tohiene and to toluene only and are all caiLMally relalivl, but we nmy (1) a« the n-.-ult of dirvct ex|H'riiiicnts with pun- trinitr(;ative result.'* in attempt.x to obtain fumt*H or volatile impuritie.H in the work.sliop, and (4) of f*«-veral per>ional obttervatioiiM of traa^itioiiH from minor TNT. illnesn into toxic jaundice, we an- .stronjjly of opinion that all thes«' eflwts are cautted by the hjime Mub,-*tance, trinitro toluene, aiidthat they an- probably closely c«)nnect«'d in their nuMle of cau.nation. Administration of pure T.N.T. to kitten.>( either by mouth or inunction ra[)idly pnuluces cyanosi.s, dyspntpa, and oficn nau^-a and sicknef.s ; the animalt an- then obviously suflerinj: fn>m minor T.N.T. poi.'winin^;. A larger dose kill.n them from acute T.N.T. cyanoNi«. Rodents show it les.s markedly, but a defjree of cyanosis is pnxluce*! hen- also. • )ne of ourM<'lves (T. .\, \V.), taking by mouth .'»0 milli(;nim!i of pure T.N.T. ilaily and not Koing near any other ex}s>!>un' to T.N.T. for a |M-rircenta(;e of impuntio have lx>en any more M'vcndy hit than worker* with the punr ijUiklitics. nor that tho«e working near molten cnnle TNT., when- then- would U- much mon- vola- tile impurities, have U-«-n nmn- ••evi-n-ly attacki-cl th.^ii !h«»o working: n-mote from such .»oun-es of volatile impurity If an impurity presi-nt only to the extent of a fni( iinn <>f mie per cent, in a factory tample of T.N.T. is to be mnanh-*! «-•» a causative a^ent of any iiii|>ortance, it must evitert-«elf have a pro|M>nionatelN morv lethal efle»t. For example, if it l)e present to the extent of one |>er cent., then in neat coiulilion after isolation it -thould be approximately one hundredfold as pniMinnu.* as T NT. and alM) prtxluce the olwervetl eflects of T NT. illneM>. 40 No sucli substance is known. We have, through the kindness of Messrs. J. Leitch & Co., been supplied with samples of all three of the isomeric di-nitro-toluencs in pure condition which are only present in small amount in crude T.N.T. We have tested these on animals and only found them of the same order of toxicity as the tri-nitro-toluene. So far as there was any difference they were somewhat less toxic. Again, samples of the various impurities separated from crude T.N.T. in the processes of purification necessary to obtain a purer product for filling " exploder bags " and for other purposes were placed at our dispo.sal by a large manufacturing firm. These were examined and tested, and none of them showed any sub- • stance pos.sessing a higher degree of toxicity than tri-nitro-toluene itself. It has recently been shown that in certain processes of nitration the methyl-group in the toluene molecule (CgHj.CHj) is s])lif oft' to a certain minute extent, and as a result the crude nitnilion product contains a certain amount of benzene-nitro- oompounds and nitromethane compoimds. These latter com- pounds resemble chloroform and carbon-tetrachloride in their chemical structure, except that instead of chlorine the nitro-group (NO2) takes a place in the molecule. They are well known to be very poisonous. One of them, tetranitromethane, has recently been isolated and investigated by JMr. F. W. Linch, chemist of Explosives Supply. But this substance is only present when cer- tain processes are used, and is then only found in the crude product to the extent of 0*12 per cent.* Moreover, the toxic effects produced by it are quite different from those of T.N.T. poisoning. On all the above evidence, it becomes clear that tri-nitro-toluene itself, and not any volatile impurity or fume, is the cause of the blood change and of the cyanosis, pallor, and clinical .symptoms >o produced, known collectively as " minor T.N.T. illness." The evidence that the toxic jaundice and liver lesions are also caused by pure tri-nitro-toluene is scarcely less clear. (v) Causes of Toxic Jaundice and Aplastic Ancemia. 1. Preliminary Discussion. — In the laboratory experiments, as vrill be recorded later, we have obtained in three rabbits liver lesions which on microscopic examination showed necroses and fatty degeneration closely resembling the early stages showing in the liver lesions in human beings dead from T.N.T. poisoning. Also in one of these animals there was distinct jaundice, all the tissues and serous fluids being bile-stained. In the workshops several fatalities have occurred amongst workers who had never been near crude or molten T.N.T. and worked oidy with the purest industrial form of re -crystallised * Tlie greater part even of this small amount would be removed before the T.N T. reached the shell-filling factories. T.N.T., w'hiih would only ctmtAin u fraction of one |jNT of caMeii in kuwill, l*ut llun- i« oiu- c'ttho (S. S.) wliin" cniiiloynii-nt on pun- T NT (uily in tilling " f.\|ilo•. >! ' i HiWl : thin wiiH ni ovrriil from in Ktbruiiry, lul", Imi (i/iy luir lontiirt with T.S T., itplaKtic iinn-niia tli-vi'lo|Mt of ImiIIi inf'X| t)Mirf to tri nitiD loluiiii-. Otlu-riUAt-x of death front apltt^tic annMiiia have ithown ..t tho auto|Mira HiniiUir le^ionH in the liver to tho!*e « hanutcrixlie of toxic jaundice. Thi> ground Uroim-.-t lci».s certain when the ()ue>>ti(>ii i^ •. ■! ittden'|H)><- t>. !■ x ■ jaunilite and aplji.-.tic annniia, and in a certain niiinlMr i-t < ■. < - lead on into thexe nion* grave alTections. No rigorous proof can Im- given, and the deeiHion, aii in many legal anil clinical ca^^eH. must In- made on the weight and Imlk of the evidence. It mu«t Im- n-mendM-red that the majority of our lieliefH in nuilicine an- n>uched by such a pnuet-i. and not by deductioits po>..Hing mathematical e.MU-titiide. The be*f plan will Ik- to put evidence U-fon- the n-ader. and diMeu.i.s the underlying physiology of the londitions induciyl by the primary |M>i.'4oning in the blooil, and then leave the judgment with him. The gnat pnictical ini|Mirtan°ce €>f the issue in whether pon-ouM distinctiv cvanosed or slutwing in other wavs signu of minor TXT. illness shoul.l U- tumid off TXT. work. If thi-n- wen- no riuincctioii lM-twe<-n i-yanowis and to\ic jaundice, thi-e |Hr><>fis might safely Ik- left on. and many -ln>ni;ly cyanosed individuals have Ix-i-n left on without toxic jaundice developing for many months. This by no means pnive« the matter, a« we shall see prewnfly. and. in the opinion of the writer, many livcM were lost earlier in thi- cnm|)Aign by this cyano>i« not iM-ing use«l i\n a danger signal. The pictun- given by us in liiUl for diagnosis an( this sign. The conjunctivn- must cirtuinly U* wat<-h«-nid to li|»s mid face the smaller nnmU-r of cas«-!» there will U* of JAundic<-Ati< What if do<-s show IS that the i yanose<| |h-p>4U) is not with a giMwl «kin protection, but i- one who hft« let in tlt« ^isoii. 42 which may now attack both blood cells, liver cells, and bone- marrow tells, either simultaneously and directly, or seriatim and indirectly. The important matter from the preventive point of view is that cyanosis and its accompanying pallor form the best danger signal we possess, that liver and bone marrow are in the firing zone, and so long as there is in the country a sufficient supply of insusceptible people susceptible individuals ought to be removed. To await jaundice as the danger signal is accordingly the unsafe course, to utilise definite cyanosis the safe one, and this apart from whether jaundice be due to direct attack on the liver, or indirect through oxygen-dearth, or a mixture of both. 2. Physiology of Increased Hcemoglohin Metabolism. — The first evidence to be taken is that for the existence of increased blood destruction as a sequence to formation of met-hscmoglobin. Tlie importance of this investigation lies in the long-continued over- work which is presumably thrown upon the organs involved in the katabolism of the met-hsemoglobin and the regeneration of the new erythrocytes. These organs are the liver and the red bone marrow, and these are precisely the organs liit in the two graver issues of toxic jaundice and aplastic anaemia respectively. The e\idence for increased haemoglobin metabolism will first be considered, and then that which has appeared to certain obsei'Vers to negative it. Increased haemoglobin metabolism need not, and in other well- known pathological conditions often does not, lead either to jaundice, or increased deposits of iron in the liver, or the appear- ance of nucleated erythrocytes or poikilocytes in the blood, or to diminution in number of red cells, or reduced haemoglobin content. All ordinary moderate cases of chronic malaria are examples of this fact. On the other hand, it is not denied that other agencies may produce any of the blood changes above enumerated. The whole question centres around a labile physico-chemical reaction going on in the blood and the haematopoietic organs, and the point at which this reaction comes into balance like a reversible chemical reaction between haemoglobin destruction and h3emoglol)in regeneration. The metabolism may vary within wide limits, as do manj- other metabolic equilibria in the system, -without materially disturbing the equilibrium point, as shown by use of haemocyto- meter and haemoglobinometer. The only set of substances which must be increased in their production as a result of increased haemoglobin destruction are the waste pigments of the body, namely, the biliary and urinary pigments. If this increase be observed, it is clear evidence of greater haemoglobin destruction because they arise only from such destruction, and they are that fraction of katabolised haemoglobin which is not utilised in the red bone marrow for the anabolism back to haemoglobin. The iron-containing fraction 43 i*) retaitiot luwl iitiliwci, anil, acconiiiigly. if aitaU^liHin it* [)ro<-«HHl- ing ax fiiMt at kntuljoliHin thi-n- iu-<-<| not Im* any occuniuUtiuii o( iron <-()rii|Miiiniix in li\'er or ••UiwIuTf. '.i Toxir Jiiuiulirf anil Aplntlir Ainrinin Mlu(^-tiun of iii^incntH will (ie|ienil on the condition ami activity of the or^nnx which uMe of th«-ni, namely, liver ami kidney If, -iiy, four tinuft the nornifil ainoiint of ha>moglohin is katalxjIiM-d hy the liver celU, ami four tinien the normal amount of liile |iif;mefttt« »o formed, i-.nd if now the liver cells exrnte out into the hile caniiliculi four time-, the normal amount of |iii.'meni. tlu-n there will Im- no accumulation of hile pi};mcntH in liver, <>r |ilii>nia, or tirtHues. The liver parenchyma will, so far as tin- r.i-k it concenuMi, hiivc to work at fourfold its normal rate, ImjIIi in the themiial hnakdown of the luemoiflohin and its after excretion into the l)ile stream. S> lonj; iw* the liver can cojm- uith thin all ^iK's well so far a.s jaundice in coiiecnM-*!, and thi- only efT«-et noticed will U- incn-a.>ic m.i\ < ith.-r l>e stond in the liver, or S4nt out at fourfold llie r.i*< ».■ i ht- red iMine marrow to supply the increased demand of tin h im.i tohlti.HtM for iron com|Niunds If the iron is held up tli< f wll l»e an iron starvation of the hicniatohlasts Icatlin^; to .uti.i : m of ana'inia, hut not to jaundice. This may ap|><-ar ' diminisheil erythrocyte |iriH|uction and in ap|M*arance of u-. and im-Kular fonns. On the other hand, if the liver di- ■.>... - the increase of iron com|Miunds info the MikmI stn-ani, ,ind tlm* in fully ufilisjMl hy the hn-matolilik.stie tisNue^, then the ntl marn»w will now also have to work at fourfold tin- nonnal rate ami may suc< t-i-d in doini; this or hn-ak down. If it Kn-aks down, then then- will Ix- aplastic ann-mia simply fn>m atrophy and exhaustion, with an enormous drop in erythnxytes luid a replacement of rf*\ hy yi'llow marrow, hut no jaiimlice will ap|M'ar if the liver U- func- lioninn pro|Mrly. Then- may also obviously In- parti. il hn-ak- •lown of Inith liver and nnl marrow functions when therr may be hoth nnn>mia and jaundice pn>«ont. or one may HiirctHHl the other a.s ha-s U-en olwcrved. lii't us consider a little mon* minutely the poisihility that th«> liver i.s not able to cxcnMe into tlu' bile stn'am the incrna.s«tl bile pigments a.s fii>t as it can form them by katalM>lisini! hn-ni-L- The effi-cts will then vary a<«-onliiii; ti> what pari I'f the ' mechanism has broken dowii If the bn-akdown i« in flic |»an>nchyma. this will Ucome bliM'kephy. after a stiniulatt. imthological n'>;eiienition. ami at this stajp* then- may t little general jaundice. If the hn^akdown i* in the bile « .n tlu-ir inen>n» «how tbi proportion •>< th't* ai wrk '•"m" !i< ton of th'- - •' ' • " ■■ - ■ ' ' • '" be f . a •>;. •veil so J, |i. J No c.ise ».iN bile tiiiRwl I leiul »lip|>«>lt t'l III'- ^ ,.|.'.-.ili 'ii til, it I S I « ikii> iii.is \f ir. .r.i;!j citiiugc til tl.c livrr without uttatk> ol MLkn!i ur toxic juuiiiiitc.' It nmy \>f |M>iiiti-(l out tluit Hiiicc the m»1o Hourt-c of bile pignicrtt in katalMilisitl lin'iii>>iii. wliiit thi- bilr Htaiiii-«l mtuim most |iii)hiihly in(li(ii(«H JH thiit tlii- iiurfii-M'«| LttulxiliHin of tlm ba>n)i>Klobiii r«-»<'lics Mich a U-vcl tliikt tin* liver rclU uinl biU< eunalii-iili nn> nut hI>Ic to \m-is it nil llinxi^li into tin* bile i-ltniiuelii without xoino Ifukiit!)' into tli<- bliMnl (■a|iillarii>s (liu> to its iiifn>(V4«Mt com'fntriitioit in irlls uml tissin* spaces. It is hpneo diniciilt to a^rc*' with Dr. Pantoii in atmtlipr M'Ctioti of his pa|M'r, where he states that :-- ■■ The daily al^Tption <>( I" X 1 . lUxn not contmonlv havcany ilclctcriou* action on the bhwHJ " Ni> tlcRrp*- ol aiixinui apprsint to have bc«n priHliiced among tlvc fifty w.ifkepi fv.iiiiiiirtt On the lonlrary. the retl cells and hf nii>t;loljiii were well up to the nuriii.il standard " Aj* has iRfh s«'t out aljove, increastMl destruction of rc^l bliKxt rorpuscles can iMciir without lemlinK to aivy ann-niiu. pmviclitl the re|>ons. In tin- majority of c.i-es. in our opinion, a lMilan«e is cstahliohed with increased destruction and incrcas«-d pnHluctioii . in the ■••mall minority of rimentally so a- to exclmle any din-ii action of the poi«i>ii on the t«o main tissues lomernetl . we h'ixe no desin' to inuiniuin that such n direct action in iin|H>ssibU>. but would |Mtint out that the two sitti« involvtHl are lluwc roiicrmvcl in rt>painnK » hltxxl (it struct ion. .\ detiniie i-«ue could only l>e obtainrssibio iM-cAii.se the |Miisitn must naeh the»e ti*suei> throutih ihv IiIimmI stn>flm and will act u|»on the erjthrocyteji on the way The last rrniaininc n'soiin-e for a dear proof of dirvct action on these ti.s«iies wilhoiit blood chang«>« i^ a negative onr, namely. 46 the supposed clinical observation that jaundice has been the first sign of attack without any precedent minor T.N.T. illness or evidence of cyanosis. This position is surrounded by all the difficulties of a negative proof. It could only be admitted where there had been most careful examination of selected cases beforehand and thorough exclusion of other symptoms. Such proof has never been given, and the circumstances are not such that it can be given. Each factory doctor has a thousand or more of T.N.T. workers to look after, and it is quite impossible that he should examine each one of these daily and rigorously, and by scientific evidence, exclude blood changes. A great many of those cases where jaundice ap2)cared to be the first trouble were antecedent to the introduction of workshop inspection or in j)laces where there has been delay in introducing it. One occun-ed recently in which it w^as declared by doctor and welfare supervisor that jaundice was the first sign to appear and that there had been no cyanosis, but the case did not bear investigation, for intimates of the deceased at her home, lodging-house, and the workshop, volunteered the informa- tion that her lijjs had gone blue, and that she had suffered from breathlessness, giddiness, and sleeplessness. (See case records below.) It is indeed difficult for a physiologist to conceive how there could be such a concentration of tri-nitro-toluene in blood plasma as to attack the liver parenchyma, cause degeneratioii of the liver to half its normal weight, and produce jaunrlice, without touching the blood cells, for which this poison like others of its class is known to possess such a strong si^ecific affinity. It may, we think, be assumed that tri-nitro-toluene in all cases attacks the blood, that tliis attack shows itself by indubitable physico-clinical signs, and that care over such cases and their early detection in the workshop is the surest safeguard against toxic jaundice and aplastic anaemia. This position is supported by a large number of the returns in the monthly records issued by the Home Office, in which it is recorded that patients in earlier days were seen to be jaundiced by their workmates or by their intimate friends at home when they themselves did not know they were ill. The sequence of toxic jaundice upon minor illness and cyanosis is also shown by our clinical oljservations in the cases quoted below. It was these observations which led the writer in October, 1916, to make the following suggestions, which are quoted verbatim from a report then .sent in to the T.N.T. Advisory Committee : — 24th October, 1916. " Living, as I have done, amongst these workers for several weeks and going round the shops and examining daily, I have found that it is perfectly easy to detect the early cases of T.N.T. illness short of jaundice. There is a T.N.T. facies that is unmistakable, a pale face lacking in e.xpres- sion and like anaemia, but peculiar in itself, lips that can scarcelv be described as cyanosed, but of an ashen-blue colour, similar gums, and (wrhaiJB a (.tint trace ol yellow uit the oinjunctiw, the real of l)w> tkio •bowing ri.) icterut In such a axac qut-it»oiimg will often elicit a hittory of h(rada4liir*>, or nausea, or abdominal (Kkin« " The two fundamental recommendations arisini; out ul these observa- tions, itre. Ill th<- iirst place, the rrni'ival. as rapidly ixs it laii lie a4.<.om plishc'l. o( the lUMcptible iiuliMdu.tl'. Ironi l N I wurk. and llwrir lepUtc tneiit )>y (rcrsli workers sent by the labour l'.XLliaIi»;<~> by priority tu T N I w'lrk I estimate thiit there are between 5 ami 10 [>er tent of peopl«- at work on TNT who should be sent to other work. ■ Ihe pitkini? out n not a duhcult task ; it scarcely even re.juire^ medical skill , there i« a foreman and a forewoman who are right nearly every time they Nend them to me " fi . .., . ,,;■ \... ,i,.i,. II. 11 !,■ {..-oplc who liavc soni-- .•« •- i .. ... - .i t' • by a vi»itiii(! surg" I ' \. itement o( Roing to il ot munition time in .' up th'- p.iti' ih' symptom* The iK-st u.i\ is !■■ •,ir,s\ round the wt k them out as they work or get the (oreman or welf:irf n'v. , n. tly to draw attention to th'«r -snspr.-trd " I'i I iiiust lie a large one and Ik I' crop iH to lie avoided The •tii. besni.i. :. must be exercised on new U'Ks: have Ih ■ 1. . u^ i^.'.i i..i over ^ year and never liad a d.i> o, , ., , m. kih-^-<. anil theM' .irr uitcn not very well developed physically or m any way resistant l>n>king " It i>4 iiliiiOHt imivtTHnlly n((f that < yaiii»i.s and jaiiiutiri- an* n-lattil, that till- •.ystom of early (Utrctioii in thf workshop tht-u btinn intnxliii'i-)! ha^ \n'vt\ a .tlu-t-t anrhur in conilMitinjj toxic jauntlit-e. Til'- |Miuliar |Millor or jjn-y IiIimmu-^-* of tin- rountj-naiue of tlii-M- |Miipli' uliifli .sitmilnti-s nnaunia m not tnutinia. ilh Ur. PantonV rfxult.H. iiml our own. .show ; it is thr nlten- yinptoin.s ^ivcn last (IiIoImt is "and jtrrhnit^t a f.iint tra«v of yillow on tlu- ronjunttivif. tlu- n-st of thi* .skin showuiK no icttriis " Wlirn thisc an. oksrrvcd thf |Mttr<>llini; surnfon tttoi** and <|U('.st loiLs the workiT. and thon hf may hear of ahniinal |MiiitH. I^iddines^. sU-epincMM, lin'athles.snt's.s. .si(kneH.M. He may tir may not elicit this history areonlinn to whether the worker U'vU like tt»f>tinn or jjoinR on with work ; if the irftfU'rver U* wise he will act mr.irly on wh.\t lie S4iw iM'fon* lu" disturU-*! or questioned the worker. It is out of the «|iie.stion to wait till general jaundnr devrlo|ts, attd the lir-t faint trace on the .s<'li'n)tics is valuable a-. contirminK the cyaiiosi'.. One must not wiiit for deeply yellow conjunctiva! iK-fon- tuniini: olT, it is too dangemus. We are well a wan* from having s«'en them t hat t here arv workers ■A for months wit hclreply blue li|tn in the»o i\.i:. ■ 1 pctiple. and they p«v«4*<',s.s n-«uaAikt Iiv»«r criLs oad rvd 48 marrow cells, but they arc in a danger zone, and the sooner they are weeded out from T.N.T. and put on to other work the better. Converselj', there are cases where, without any cyanosis so marked as to have attracted attention, jaundice had appeared apparently as the first symptom. It is here to be remembered that some skins show ( y^uiosis more readily than others, and that the same poison in diilc rent iiidivichials may hit the two types of cell, viz. : (1) red blood corpuscles and hsematoblasts on the one hand, and (2) liver parenchyma on the other, in var\'ing degree. This is well known for other toxic substances. Wljile the cyanosis in such eases was not apparent, we have little doubt, for reasons already given, that it was there, and would have been found had it been carefully sought for l>v blood examination. On the other liand, there is no question of the frequent associa- tion of cyanosis and jaundice, or of the large number of cases where cyanosis appeared first, and later the jaundice. Several cases have been sent off work for cyanosis and minor T.N.T. .symptoms and have developed mtfrked jaundice at home. In other cases, accompanying cyanosis and the minor symptoms there has just been the faintest trace of yellow on the sclerotics, and a few days after, the patient being at home in the interval, there has been jn-ofound general jaundice developed, leading in several cases to a fatal result. One difficulty is the small number of cyanosed cases wliich go on to jaundice, but widening the outlook on the field of medicine affords parallel cases. Chronic alcoholism, for example, is, like T.N.T. poisoning, a prolonged chemical toxic action, but how few chronic alcoholics pass on into cirrhosis of the liver ? Lead poisoning is a slow chemical effect, but how many lead workers, with the blue line on their gums, pass on to the other classic symptoms and to death from lead poisoning ? Another point urged against the relationship is that, while cyanosis can be pi'oduced by the exhibition of pure T.X.T., it is not possible as a result of chronic poisoning in animals to produce the T.N.T. effects on the liver. In reply, we woidd say that we have actually produced these effects as already mentioned in one rabbit by administration of pure T.N.T. where there was marked jaundice, and in addition the liver afterwards was examined for us bj' Dr. Turnbull, who described the effects as similar to the early stages of attack on the liver in human cases. In two other cases of experimental pure T.N.T. poisoning, also in rabbits, well-marked liver lesions of similar tj^pe were obtained but not accompanied by jaundice. It is questionable whether a larger number of positive results than this ought to be expected amongst the numbers of animals experimented upon. As every pharmacologist knows, it is notoriously difficult to re-produce chronic pathological lesions experimentally in animals by the use of drugs. The adjustment 49 of the dosage ami ifH variiitioii with the ilumliuii of the ex|KTiiiiciit uii- very ilitficult to ac-eoiii[ilii«h with the iiievty required. .Moreover, we kikuw fniin our workxho]) n-M>«l ihnmnully to TNT only one or Hvn (lcvflo|i jaintdiee. Mow many |»<>sifivi' r«'sult» may then reii-.iinaljly lie oxjKKrt*-*! ainon>{st fwo or thn*' doZii-n animaU ? Nor ean the reHults Ix- ha-dem-*! I>y a relate the case-, w hich caiiMMi iw to adopt the view that cyanosi.s and jaumiice were intimately connected, and to atlvocate a-^t a result early detection in the actual work>«ho|iM. Cast I (Ki-cunled l.y II M ) NV <). It wa* while wurkiiu. ilailv at in S'-ptcmtirr, hUH. that my i"' ■" .. .. .1. . ,. ,. i., , i . i ..i, \v. i, ,,j Sii|»crviV)r. Miss Vork. t.> this j.; : ;.^ and th<- |h-<. iiliar |>.»lliir in .1 mail. .r nclcrotitH. t)n (|ucKtii)iiinK, sU>- .. ;..it she Iiail » certain ammint nl nausf.i. \<\\\ had u 'l Im..-u :.i.,k.. .lud lluit she bad slit;ht alHlnminal (kiinit, l>ul iinthiiig, mIic acldr --h'- niii^t ii ■! .l.iil \s 1 k .i^^uu Iw.mi' \.iii n this Rirls "ulerDtics ; I had not it oiur M-nt oti home, anct I ti>l «-e me nn tl„ .'.; , . te A« villiiw ai fsninean. and she lutd a Rri. v .n iiiiiiK-ihati'lv -enl inln hospital iimlei t At tif.>t sh<- qilitr hiiKht aiirl ihrerfiil l>n t\v 1 ull. 'f »hr talke.^IIiiij: fiiui ! !,. r d'tiri.niH i %«• .liid died .\t th. l.lKudl.r du.- t- 1 M* ..I iv.ui..^i- .ind t e ('d<' // F. S The above cMT finit •wakened mr tn the .1- • thf-^^ mw-i <^»rlv .ind ! nsk«-H ff-rrmen ai>d (..rrwMiii. :; ...... . ,,, f;..iru; "l< .■.•!.. ur. .!■ ~« Th.H i;,tl %va» ^r„. ..I W ( .w I ) > , : ;.>lr 'n|n. I>tit with a very lia>< Muuktlh aktii. antl tttcic wiU it Uighl Uut so quite distinct yellow tinge on the sclerotics. I had her go away at once to the hostel and be put to bed. Two days later I saw her and examined her carefully. The yellow on the sclerotics had definitely developed, so that it was quite obvious at a glance to anyone, and there was a faint, but quite definite yellow on the unexposed skin area of breast and arms. Fortunately, things did not go beyond tliis stage with tliis patient. In about a week both cyanosis and jaundice cleared up, and the change in complexion was most remarkable ; her delicate skin was now white and semi-transparent, with a perfect pink on the cheeks. The change from the muddy, greyish-yellow to this was most striking, and was com- mented upon by a lady visitor, who had seen her along with me when she was jaundiced, and again a week later when she had recovered. Case III. — (Recorded by B. M.) E. C, a young girl, one of four, whom I took ofi on the same forenoon in October, 1916, employed in filling exploder bags with pure T.N.T. This is a case wliich I insist ui)on, and emphasize as of the utmost importance from the point of view of settling definitely the true causative agency in the poison causing jaundice and proving it to be trinitrotoluene itself. The actual T.N.T. in use by these girls was a very pure commercial sample, almost colourless, crystalline, perfectly hard and dry. There was no molten T.N.T. anywhere in their neighbourhood, and no fume detectable, except by a slight bitter effect on mouth and nose. In view of the intense bitterness of T.N.T. this sensory effect cannot be taken as indicating the presence of any quantity of fume or dust which might be toxic tlirough inhalation ; our experiments cited above disprove this possibility. There was nothing present here but T.N.T. in hard solid form. I inspected, at first asking no questions, a gang of about thirty girls, and, separating four on one side, by questioning found that they had all had the well-known symptoms of minor T.N.T. illness. I then sent them to the certifying surgeon, who stood them all off T.N.T. work. A most interesting point is that the gang were all alternating their work, and all, including these four girls, had only resumed ivork on T.N.T. that very morning about two hours before my visit to the workshop, after a full week's remission on black powder work quite free from T.N.T. Next, as to the symptoms on which I detected these four girls ; these were ashen-blue lips and gums, a peculiar pallor of their faces, and in three out of the four cases a slight yellow on the sclerotics. The most impressive appearance was the blueness and pallor, without which one ■ would probably have passed over the slight yellow on the sclerotics. But, as one is ever on one's guard for the first signs of jaundice, when- the other signs are there, one looks most carefully at the eyes, and then in many cases sees a faint trace of yellow. One would not " stand off " individuals with little or no cyanosis and pallor on such a trace of yellow alone as these girls showed, under present conditions of admission. Now for the subsequent history : within a week off work three of the four, namely, the one who had no yellow tinge on the eyes, a dark- complexioned girl of fourteen (E. M.), and two of those with a slight tinge (M, and L.), quite cleared up, and the change in colour of lips and cheeks was most remarkably striking. The fourth case (E. C, fair complexion, sixteen years old), is that upon wliich I wish to lay most stress as showing the connection between cyanosis and jaundice. Let it be remembered that she was working on the purest form of T.N.T. used, very much purer than that used for melting and making any form of amatol. When she was detected by me she was cyanosed, pale, and had a just definitely detectable tinge on the sclerotics, but no general jaundice on unexposed parts of breast or arms. I sent her. like the others, to the certifying surgeon, who " stood her off " like the other three, and sent her into the nursing home. Two days later I called and saw her, when she was jaundiced quite distinctly all over the body. Again I saw her a week later when the jaundice was fading, but still distinctly 61 prnwnl The cyuiKiftis and |ullur luid liy tlii% tiiiii? y.: .1. The jdundlcr clcarey the irrtifying aurgeuii, Dctober ISth. li»IH (ate II' (Rec<-r)iap« so pure a.s tluit u»etl by the girlii dr«|>earance« only. He wait then niarke«lly cyanused and pallid, and had a i|iiite distinct icterus on the conjuiictivx and a slight general one on the skin Only ' r tiim r the last two weeks, and that he had l.itcK ly I><>ttor and l>een ofl work (or a week, since when he 1. 1 »i work (or ten days He liad no intention i>( going to see the doctor liecause he had had this week o(T so recently, and we luiil some diflTiculty in arousing him to the fill t that he was seriously ill and must leave work and go tn the doctor at once. He was sent to the N. Inlirniary by the terti(ying surgetm. and we saw him there two days later ; he was then deeply jaundiced, but did not complain much, and talkeme Office as a case o( toxic )aundire. date Novcmlx-r 9th. IHlii ; occupation, weighing TXT. in l*rewi House; duration ol rinployiiunt, three months ; severity, severe : remarks, vomited November Stli, continued at work till tletected bv Surgetin November mh. still declared he felt all right. This cxse illustrates again the connection of cyanosis and early jaundice. Can r. — (Recorded bv U. M. and C A. W.) K . male, aged 32. Trucking to cylinders. Melt House ; November 29th, 1916. We caught this c.vse in a curious way — just one day before our visit t.' the fact. TV r.>n.Iiid-innr> u. rr.jiiired in aU^ul as many minutes. We look notes of the condition and employment of each man wjio contributed, and K. was one of thcae He was markedly cyamnsed on the li|M. and also showeti jaundice, not only on the eyes, but on cheat .111.1 .■\t>.t. mrn 1 01 .11 '>t. It .. Kat hlin »•■ ii..im-.- rir w.Mii.i i;' ' "'■ -l"-< •iii'-ii 'i 'i'> >"ii" ..n.*.., .. i.igb content ol altered TNI (equivalent to 3 on our scale) We did not ourselves see this patient again, but he was returned to the Home Office by the Certifying Surgeon of the Factory as a case of toxic jaundice, and we quote the ffiUowing from the monthly returns of February, 1917 : — K., male, 32 ; date of disablement, 29th November, 1916 : precise occupation, filling under cylinders ; duration of employ- ment, 4i months; severity, slight; remarks, October 17th symptoms, severe gastric catarrh ; suspended until October 31st, when allowed to resume at cylinders. Again suspended November 29th (this was the point of our intervention) until January 3rd {i.e., for five weeks), when returned to another part of factory. January 10th, suspended for continued signs of jaundice. January 16th slight conjunctival jaundice. At sus- pension on November 29th his whole skin was washed with acetone. It is clear that this patient had minor T.N.T. illness prior to appear- ance of jaundice. It is interesting that in this history supplied from the Factory to Home Office there is no mention of cyanosis, either in the period of his illness prior to our detection of him, at this period, or later. Yet when we sent him off on November 29th he was markedly cyanosed. This is not said in order to tlirow blame on any observer, for cyanosis at the early stage in these jaundice cases may be too common to mention. Summing up on these five cases, which are our own personal experi- ence and detected in the actual workshop when they had no intention of reporting ill, we would point out in the first place how clearly they demonstrate the value of early detection, for we feel certain that one, if not more, would have perished but for our detection. In the second place, the universal presence of cyanosis in cases caught and observed in the initial stages and the importance of this sign in attracting early attention. Case VI. — (Recorded by B. M.) F. W. Weigher to Pellet Press. This case occurred at a considerably later date than the previous five, and is here recorded to show the fallacy of accepting without thorough investigation negative evidence as to absence of signs and symptoms other than conjunctival jaundice. I was down at the factory where this fatal case of toxic jaundice occurred, endeavouring to perfect a mechanical contrivance for keeping the girls' hands out of contact with the powder in one of the most dangerous forms of T.N.T. employment, when it was reported to me that one of these very girls was then in hospital seriously ill with T.N.T. poisoning. I had been told by the Works Manager and the Welfare Superintendent that the very first thing noticed was the jaundice in the eves, and this without any premonitory warnings, thus showing the impossibility of catching early some of these cases. The same evening 1 visited the l-"actory Doctor and heard the same tale. I asked specifically if cyanosis or other signs of T.N.T. illness had been observed, and was definitely answered in the negative. The doctor told me he had seen the girl on his usual Wednesday visit three weeks previously. The only thing he detected was a faint yellow on the sclerotics, and, cross-questioning, failed to elicit any admission of symptoms of T.N.T. illness. He did not send her off work, but said she was to be kept under observation. On the following Monday she was sent to him with much deeper jaundice on the eyes, aud with slight general jaundice, and was then sent to the nursing home. Here, then, seemed to be a typical case of jaundice occurring first, unaccompanied by cyanosis and other minor symptoms, the sort of case upon which those medical officers rely who hold that (1) minor T.N.T. illness and cyanosis, and (2) toxic jaundice are distinct clinical entities. Being on the spot, I determined to examine thoroughly into the evi- dence of this seemingly foudroyant case, and I interviewed her relations, her co-workers in the same shed, aud her lodging-mates. These, without any leading questions whatever, all ooncordantlv vohmteered the informa- 53 >n tlut her li|>ii luil i;f>iie blue (ur nearly 4 (•jftiiight bcltfe. ttkal klie lutd •iiiplaiiie«l o( KtililiiirM. had »hown ■tlrrpiiKiu and Ltuttud^. and in the - i.-w .lav, t..,l u-.-„ l„.-..i,l..,, -,.,,1 ^ .r.^iv able U. walk tbeam li 1 atlrndnl. and it «ra» I t>y I vani«u and all the IIrt^- »M-rc ■ - • ,ted '.3 ■,wn tiuh ll .>.i!. ..%:-. i.l the It mu!tt tte done 111 Ihtr worlohop b«-'--''K ... ■■ > ..■■ .ij.,. ,. ,,.. ,.,-..•...••.■■. .......... ..,,., . aiiiica flu-.liiin; "1 l.ur and iiin Tliin a|>|M-tirs to luivr licrn \vluit«luippcncd in this case, the same reti- ecucv, ami |«Th.ii>-. .1 Icir of licin^; turned ofl work when she did not leel b'rstll ill inmii-li fur that, seem to have complicated the tituation and m.nli- tur diny to the doctors tpieries even the Kanty information she gAv in her lodKinc^ in. I .if th. f.i. t.rv Til.- i..|l..wiiu; . On 1 1,.- Sim.l. 1 visited her at til.- Niir-.iiu: li I nbvtoiitly ds ''■ ^' ' ,..^ i.. .1. ..I I... .11 ..II eyen and *^.. • . k» previously, but she liad not n ■ r ri-l.iti\.> I «... ! 1.! tl,. N M.I. in II. ■ . r t.>..!u. ft;ul I w,ia .it min- .mil inttTN r(H-\ were a brotlu-r and three Hintrr* I ni.- I'.'f.mir tt..--v ti.i.I n.Mi. .,1 n. tl„-jr sisf. : ^ .n.l wriit t' t told ma t t».. visit* r' -'inf •!icr .1 vmt .■vnv ju.-.M :. t .i:u .4 tliini. cxtciil my ini^.i.^l ..ne \ft*Ti\ . .n I inV-f. i.'u. .1 .1 i;irl M K vvl... «.->^ th.- .V. ca*wl :<-d. but would not go home and I |. in .. |..iU ... t,^r i;„| ,|M •■r v..t f.> I . tlir <|.wt..r Mir ».,s . 1.^ f tired, slevpy, and ahort of breath 54 Confirmation of this statement was given at the inquest. The deceased girl's sister, N. W., at the inquest stated again that she had noticed the blue lips and mentioned it to her two other sisters, who agreed and said she was also short of breath. She could hardly touch food, and was very sleepy, but persisted in saying she was all right, onlv short of breath. A girl working on the same machine with her gave evidence that the deceased had complained to her of giddiness, and she had noticed her lips had gone blue a week before, and on the Saturday afternoon previous to leaving ofif work she had been giddy and trembling. Clearer proof than the above of cyanosis and oxygen-deartli pre\ icus to the onset of the jaundice could scarcely be adduced. V. Prophylactic Measures. (i) Early Detection of Cyanosis. The researches and observations recorded above seem to furnish not only a sure guide for the introduction of i^recautiunary measures, but show liow unnecessary expense and fruitless employment of skilled labour in such a time of dearth may be avoided. The importance of early detection of the preliminary stages of T.N.T. poisoning has been throughout insisted on in this report and the methods have been indicated by which early detection may be ensured. (ii) Ventilation. We believe that if a dust -extraction experiment be made beforehand, as it obviously ought in each case, it will be found that many proposed schemes of forced ventilation need not be carried out. The vast majority of T.N.T. workshops are clean, airy, naturally well ventilated, one-storey buildings, in which our analyses, as far as thej' go, show tliat the quantity of T.N.T. dust is negligible. (iii) Prevention of Skin Absorption. The knowledge that the main absorption occurs through the skin of the hands indicates three lines of action, namely. (1) keep- ing all that the hands can touch clean, (2) protecting the hands, (3) detecting those hands which are permeable and keeping their o-wTiers off T.N.T. work. 1. Provision of Shell Filling Machinery. — The realisation of the skin danger has produced a remarkable change for the better in recent months in many factories ; this has far-reaching results in other directions as well as the hygienic one. The provision of machinery for shell filling is, of course, considered a matter of the greatest urgencj'. Not only will it enable each worker to avoid much hand contact with T.N.T., but in addition the greater speed attained will allow very large numbers of workers to be set free for other national work, and lead to gieat saving. Another point which may be suggested is that the most inti- mate relation should be developed between the different factories, so that the quickest method for a given operation used in any one place may be installed rapidly and efficiently l)y means of demonstrations given to the others. 5S 2. Frttteetivt Clotkimj, (ilov|M-,iiH in the urine. Thf niowt obviouM (irKt thoii^^ht is to cover the lianiiK with ini|M'rviuu.t j?loves, and we havr «|)ent muth tinio in tl*-{ning gloves and K'ove utturhinints of variouM kimis and of ililTt-n-nt matt-rials ; these all lin>ke ilown in prat^tice. We louKl protect ourselves and did do so (or an entire week while working in a hhop, and we coulil protect wurken< under ex|>erimei»t whom we our selviH arrayeti and di.-uirrayed from their workshop io<)tunier<, but our In-st attempts to drill a band of workers to earry out the»o o|HTations for themselves failed, (hue the TNT. n«ts under- neath the iflove, as it tl;loves hitherto tried, they an- worse than useless, for the inner surf(»om.s from candeo.- handling of l>oots and costumes by the workers, .\lter nat»«»J workers have two s«'ts of clothing, one for ■" i>(T '" and oive for ■■ on " T.N.T. . the.s*- ought to Ik- kept in sepjirnte cloakrooms with sejHirate access, and ins|)ection maralions witit damp amatol |M>w4ler leiwling to damp clothing nn- now fortuimtely much mon< ran« than formerly, thank" mainly to the apprt-ciation of the fact that illneKs is pnMluced fn>m Hkin I. intact aiul that accordingly th<' o|M>rations must U' con ducted with as gn'at cleanline— « iw iMxsible. For this reoMin it is only in a few instances thiH "verills or apn>ns of waterprx)ofe»l material need Im- employed, and an overall or blouse of Uuler house cloth IS Iwi-oming very common in the fartorie"! ami is \vr\ jierviceable for its pur|x>se A« to the makeup, the " bloomer " suit has l>eeome very jiopular for women munition workers anomers and a blouse is now in very g«neral u.m« 1 'Miers ought to l>e inadi- shorter in the leg^tbanat pronent , • . . II 1 over, mo/ III. lone Wi-llington l>not<« Such boot* w»m 56 introduced at certain factories and have proved a great success. The skin of tlie girls' feet, which used to be quite yellow from T.N.T. absorption, is now clear of it. At three large national facturics visildl by Ihc writer quite unsuitable footwear was being worn by all the girls, in the form of low, open shoes, leaving the doi-sum of the foot epvered only by a thin stocking and so exposed for the T.N.T. to fall upon it. This is quite an unnecessary area of absorption to add to hands and face, as is now generally admitted. 3. T.N.T. Solvents and Protective Varnishe-'i for the Stin. — Prolonged experiments have been carried out by B. M. and C. A. W. at an explosives factory on methods for protection of the skin, either by T.N.T. solvents, or by protective varnishes to keep the powder off the skin of hands and face. The results have been most interesting, and, if properly applied, ought to ensure^a great degree of protection, not only to T.N.T. workers, but to " tetryl " workers also, who have suffered greatly in the past from dermatitis. Our thanks have been expressed to the directors for per- mission to carry out the work and for much kindness during its progi-ess ; we have also expressed our indebtedness to the works manager, and to the nurse at the works, for much valuable assistance. Xylene Washing of Skin. — As washing of the skin with acetone, a solvent for T.N.T., had, in the cases of workers being taken off work on T.N.T. with severe symptoms of illness, given beneficial results in the opinion of several observers, an experiment v/as started to observe the effects of daily washing with a T.N.T. solvent upon the colour of the hands, and reaction in the urine, of a band of T.N.T. workers. The underlying idea of the experiment is that, as T.N.T. is practically insoluble in water, the ordinary ablution with soap and water at the end of a period of labour does not remove the minute particles of T.N.T. from the skin, and thus the worker is not only exposed to the poison during the hours of labour, but the absorp- tion from the reservoir in and on the skin goes on during the hours of recreation and repose in the ea«e of the susceptible worker. Jt was thought, therefore, that if the hands were soaked in a good solvent for T.N.T. at the end of the day"s task, a good portion of tliis T.N.T. could be washed away and the su-^cejjtible worker be spared a considerable amount of absorption during the rest period. This would show itself objectively in a decrease of the stain on the hands and in a diminution of intensity of the characteristic i-(^aetion in the urine. 57 A liarnl of tweuty-four k*''!'* wiu* iu.-cuniiii|{ly M'lvctvd, uiul ttfltr ili-tfriniiunt; the de^ret- of iittciiMity of tht* urinary n-iutioii f<»r TXT., tlu-y wt-rv ituttnu-tcU to wil-Ii tlnir KaiuN i-.i oil l«-iiviii|{ otT work uitli » inixtiirf of tiic xyl< ii)-< ri-<-oiiii to iiM iis it j{«mhI TXT. tolvi'iit \>\ l)r. Ct. lUirmr ulirr v\\ni n tioii witii M>vi-nil Holvi'ittH. Ai-t-tuiiu uiid Hcvoml othtr moUlmiU an- l>i'.rn*ui|>|>oiiitiuK. The Hulvent ap|icared to dimiMJoh fomowhat thr f uriiiury n-iniKni liuriiii: the fortnight on T.X.l'. M*i ua^hint; hAtl taken placf tin- liuun>s are niven below. (Appendix D.) It iii.iv \» tl..ii tlii I. Milt I- dui' to the particular -.olvi-nt u-.*-*! (\\l ' . ri of ipideriiil-< iiinii- iMinii-ablc a>ioii> who ei>nliiuie to Ix- i'X|H>M'd to T.X.T. daily, and they oujsht at oiuc to Ik- cut olT a.-i lompUtoly tit pi.- ihU« fn)tn all contact with T.X.T. in clothing; or .-.kin. F.xfHrii luc may show whether the acetone treatment i> of value for n\ic\i cn.Hejt. Frittittut Varni^ihimij o/ iSiifi wilk Casein Varnish. — Our attention next turned in the dirretion of cnatinf; the skin with umie imfxTDiealile varnish b«-fon' starting work, whiih could !)«• wi-^hfd of! or removed Ity solvents at the ciul of work, m> carryin^ Auay any TXT. with it. An imp«Tnieal)lc vanii^h. in.'olub!e in water, wa» lir»l triinl in the form of a solution in appropriate Milvciit.s of aeetatc of iillulosc. but this vamixh m-i'led and |Hirtially enicked urt. • X()o»mu the .okin, and a similar fate fell upon euiludiun and ■ uu.okiii " vaniiftliesi. A water >oliiMc varnish ouiteevtitl itM'lf next, which would »iniply wa.sh olT with water at the concluxion of work and at ih« »ame tune float ort tie '"' ^ ' ' > ■.' with it. At tin Mr Artliiir Whitticid w ul he hel|ii-«l \u u\ by «imv'' -""i! "cvi ml ■ if water fioluble v.n , »moht."-i iliem 1' I !;i'' " cawin vami«h " ■>! ilie rTiii-h I'liitini.k' at to in- fat and oil frii*. ThiA f.rep.-vratioM wn- i i>\ .i In m v \.'"ii.j' m, ui.i ■■.•i the rrsult of iK'V. ral wi'v^- ' • xccUent rrnulLs. An ex|x.riii ui.ide «t another factory, ami . . ef ih« country uv notr roiixiiicB>jnK to uar it. 68 Experience may indicate in time a better " body " for the varnish, and it may be necessary to work out something which will resist better in hot weather and not be removed by per- spiration ; but the experiments have already shown that for dusty types of T.N.T. employment, such as "exploder bag" work, protection of the skin of face and hands by a varnish is feasible, and that when the skin is thus protected there is a great fall in the amount of T.N.T. in the system, as shown by the urinary test. The improvement is visible to the girls themselves and to the nurses. Some girls stain much more heavily on face and hands than do others, and we have taken purposely the very highly stained workers and seen the stain under the use of the vai'uish almost disappear from face and hands in about a fortniglit to three weeks ; at a later stage the urinary reaction falls off. Details are given below. The preparation also protects against " Tetryl " stain and has been found of great service in " Tetryl " dermatitis. It is not unsightly in use, as it sinks into the skin and disappears. It has at present one defect, that when kept it tends to thicken, and then sometimes lathers and does not become in- visible on the skin ; when this occurs some of the girls object to applying it. Also, on a few very delicate skins there have been complaints of slight tingling after its application. But in all cases it protects, and a slight tingling or its showing on the face is a small discomfort compared to a dermatitis. (iv) Removal from T.N.T. Work of Persons Specially Susceptible to the Poison. Some difference of opinion appears to exist as to whether the same workers ought to be allowed to remain for many months engaged upon T.N.T. work on account of the danger of the prolonged period of absoqjtion, or whether such individuals have proved themselves insusceptible and ought to be cherished and retained. The answer depends on the health history of the individual. A person who has been upon T.N.T. work continuously for, say, a year or more, and has never shoMii any signs of T.N.T. illness — and we have examined many eases of both sexes of whom this is true — such a person is a most valuable asset to a factory, and should be preserved most sedulously. On the other hand, a person who has been ill more than once during a working period of, say, five or six months, with minor T.N.T. illness and been " stood oft' " work on this account, should be watched most carefully and " .stood off " at once at the appearance of any considerable cyanosis. Li fact, if we had our will we shoidd gradually remove these people who are evidently absorbers and susceptibles, for there are plenty of non-susceptib!es to carry on all the T.N.T. work. Our experiences leave us little doubt that an important factor in the recent improvements is the gradual operation of a natural " salting out " process, whereby an industrial " selection ')! tli<- liilrii " f'tr Mm ptirltruUtr tn-ik ltiw< txiiirn-*! TliLt natural t«'U(lrai y, iiiaiuktfftufnt anrkiii|4 tom'lhcr, HhouM try to i»c-cflcr«t«< by n-iiiuviii^ the hu-rtt-ptiljUw um rapully ad tho fxi){fiuif>t of latx>ur MU|i|ily will allnw. To iMMiixt thftii ill tlii-i nil tiiilcMVuur nhuuld U- iiuwli' l>y tlioM- in clutrge of l>our HU|t|)lif.t to ilirfit ii ntront; tidi- of oiicoiniiig lulHJur toMunU T.X.T. Sucli an effort will Utotni" more «'ffeftive tut the conditioiu of TXT. (K-ou{Mttioni ljf ii4 » natural liy(;i*'ii>i° Htn'ant which i^ tondinx to n-move • fear of TXT iI1iii-s,h, ami will stfotit thi* idt-a of ilaiigt-r to all lifarcr> inside and otitsidt- tho factory ; thi- «»• havo M-fii |M-r><>nally in liundn-ds of tat*'*. On th«' otlu-r hand, if thf workrr i> a MitstH-ptihU- and i> ftfling ill and tni^<•ral>ll■ whilf at work, and ha.-* fn-ijufntly l»roki-n tinio from minor T.X.T. illne».H and ln-en off on " coni|M>n.-ay." tlu-n that worktT in an uanound wononiic {)ni|Kwiti(>n fn)m the factory 'j» point of view. The liitltT ly|H' of worker will natiimlly tens.s4^-fvs a far Ix-tter " rgiltetl " .st-t of workirs than one just startini;. This IS dearly KCt-n where the illness and irritation rausctl l>y a work siil>stance i.s more acute and gives more di»comfort and Mtiffvring -a work Kubfttanco. for example, cau.sing such «'ffect« is ■■ tetryl, ' which s«-ts up in a large pn>|K)rtion of U-ginnepi an acute inHammation of tlie skin and mucous memhniiies. and iiNlcma under the eyelids. Some |M>ople U'come inund in a few daVK, othen* never do. and after suffering fmm seven- dermatitiH for week.s have to give the work up. Fortuiuitely, then* is no coiLstitiitional attack la* in T.X.T. When a new •■ tetryl " workshop is starteil with an •• um^iltcd " wt of workers there is always a hiisy time for a win-k or two for the medical staff ; in w)me ca.s»-s the whoK- shop ha.s hail to clr>M« down for a few days. Then for sonu* wii-ks or montLs there is a ctinMiderahle amount of dernmlitiii, which finally die« down alnuxit to zen>. Tiioso who have Utles.s Ix-on hap|iening in n letut obvioiui way uin..nk;si T NT wrkers. A prophyliutu iini»-un- which ha* rrcrivwl • ven- wide- -ppMd nppliiation in th'- iam|Mign against T.X T. iioiMming in 'iiA* 1 iii^nn AM "alleniation of litlHuir." a plan which ha.i luivu to .mIiiuI that till- Iji'tter ruiulitiuiut uliit h ixiitcd furiiitrlv at tiie aller- luitrtl " fuituricH might in rvuhty huvi- Ufii «e« ure paid <>n pie<.ov«oik, it ij< commonly d<-lented. It may lie ^uid that thi-^ ({uestion of output Uoa nothing; to do with the hy^itui't'-. tik.^k, and ut lirst Might thi» would upiK-ar tu be true, hut in aiis < a-e it is a mait im|>ortiknt luitituuil question, ttiid further <-sorption of |>oiHon. The more ^killed a worker become;* the \vns iiu'nn that worker mukett, uud lestt mesh meaiut lens iufoetion for everjoiie com'enietl. Also, if !<|Ki-d of working if* inen>a«itl. say, 50 jter cent.,* fn>m the skill that eomes fr»>ni continuuuH labour, then two-thinls of the op«'nitive« will do the same amount on a shift, and the double sets of ' off " and "on " workers will not be re>«or(>tion for the reasoiLs already given. What, then, is it pro|)oserken<, and iiurea.sed amount of " salting out " or rem«>ving the su.seeptihie fttrmuntntlij from T.N.T. work. VI. Treatment ok C.tsBS. It ought in thi- future only to Ik> in rare iiLstAnce* that ca«*« |MVi.H unnntired through cyanosis into toxic jaunsentiid to attend to is a comph-tc tl from all sourcc« of T N T For this puqH)««e it is not sunicient simply to give iii«tnirHoii ti> the patient and M-ml him, i>r her. home to n-lativcfl. Til'-' |«<>ple and their friends have lif' • ' -n of the !■< riMii-ni -s of their illness, and for this !• ide light of j;.'ii\ whi''h h!\\- '•■ jt^vhI f... ,• \ ■ •■ a h 62 clean cut-off from contact with T.N.T. It was only continued experimentation on the effects of (1) week-ends, (2) holidays, (3) alternation, and (4) the study of the decline in the urinary reaction in patients " stood off " T.N.T. work, which taught us this lesson. The T.N.T. is carried home on hair and hand.s and clothing, so that not only are these people subject to contact during working hours, but their homes, or lodgings, and their furniture and bedding become contaminated with it. As a result we have seen the skins of infants and little children in the homes, who have never been near the factory, dee])ly stained from contact wnth the persons and clothing of their parents, and the hair of wives stained the characteristic auburn brown from powder comiuuiiicatcd from their husbands. Also we have seen the stain on bt'd-shects and pillows. This must always be borne in mind in treating severe cases of T.N.T. poisoning, and especially when any jaundice is present. As a rule, such cases ought never to be treated at home, but in a hospital by a physician possessing some experience of T.N.T. cases. It ought i^articularly to be emphasised that this is true of the first few days of incipient jaundice, for at this stage the case looks le.ss serious than it does later when the jaundice deepens, and so the physician may be inclined to risk these few days, to see how the case develops with home treatment and ^'isits to the con- sulting room. But these few initial days are the all-important ones, far more so than those after the skin becomes deeply jaundiced, for then the physician can but watch and wait, and is powerless to give much help in the struggle. The first appear- ance of jaundice shows that the compensation described above has been surpassed, a stern fight is going on between processes of degeneration and regeneration in the heijatic parenchyma, and degeneration is slowly gaining so that there is no longer enough sound, tissue left to carry on the metabolic functions. A little longer attack by the poison, and the descent will soon become more rapid. This is the point at which the prompt action taken by the physcian in completely cutting off the supply of poison makes all the difference. The patient should be removed at once from factory and home surroundings to a nursing home or hospital. Every stitch of clothing which has been near T.N.T. or in contact with the patient's body previous to the purification now to be described should be removed. The patient should then be giveii a warm bat h, dried, and the skin, wherever it has been exposed, thoroughly cleaned from all trace of T.N.T. by scrubbing with pledgets of cotton wool soaked in acetone or ether until no pink colour is shown with alkaline alcohol. Special attention should he |)aid to palms of hands. The nails should be cut short and carefully manicured, and the roots of the hairs cleaned, especially on the scalp. The patient should then be put in bed in an airy position and given a purgative. The bowels must be moved as soon as 63 Iio«Hil>li», and kej)t open. Tin* uni\ar\' s^orptii>ri and p«T»pjni tifxi oiitrht tUfix (<> \ni Htiinulutrd by a Miiiplf naiiiu- mixture, and iluK »hould Im> kept up for two or thr»-<' dayn untd Webster '« rt-jution in no longer obtained in the urine, and the tent remaina ni'kMtive even after thin diuretic and diaphoretic action in di«- (Mt, tinned. VtvxU ve^etftble (ooen air treatment in be»it; there ought not to be ko much exercise an to make the patient breathlei-<, but nuHlerate exerciw) and Hitting or reclining in the 0|mmi. In a few days thcRe ca«e« clear up as the met-ha-moglobin break.n up. If any cyammetl ca*ie Ix- allowed back on T.N.T. work, he or she must U- can-fully watched and a n-hnuld be allowitl to continue at the work. No |N'rson who ha.s ever had toxic jaundice in under anj circumstaiues allowed back to T.N.T. employment or work connected in the same fncton' with TNT labour. APPENDICES, TABLES, AND PROTOCOLS OF EXPERIMENTS. APPENDIX A. Effects of Cessation of Work (1) at Week-ends, (2) Holidays (four days) and (3) at periods of Alternation of Labour, upon the Amount of T.N.T. passing through the system. The figures stand for the judged intensity of colour in the Webster test upon an arbitrary scale, and are in many cases the agreed judgment of two observers (T. A. W. and G. A. W.) using the test daily so that they are cumparable amongst themselves. Table I. Effects of week-end rest at Messrs. 23rd, to Monday, September 25th, 1916 from Saturday, September All girls. Reaction. Reaction. Girl. Girl. Before. After. Before. After. Brought Jorwd. 92 66 4 3 29 4 1 2 3 2 30 ] 2 3 4 4 31 4 1 4 5 2 32 3 5 3 1 33 4 2 6 4 2 34 4 1 7 3 0-5 35 3 2 8 3 4 36 4 1 9 2 37 3 2 10 2 5 38 3 0-5 11 2 2 39 5 4 12 4 4 40 3 2 13 4 2 41 4 2 14 4 3 42 3 1 15 3 1 43 5 I 16 3 3 44 3 17 3 1 45 2 2 18 4 3 46 4 2 4 2 47 3 0-5 20 3 3 48 5 1 4 •21 1 3 49 3 1 1 22 5 3 50 5 3 2:i 3 2 51 2 24 3 1 52 2 0-5 -5 5 3 1 •JA 3 3 Totals 52 174 101-5 27 3 4 0-5 3 28 Ay. Rn. 3-3 2 Carried Sorwd. 92 66 Notes. — The intensity set down at the value 05 is what we customarily called a trace, and is equivalent to what would be obtained when 5 to 10 milligrams is swallowed, and a little less than is obtained during a shift in the case of a careful worker with completely protected hands. It is to be observed that no worker was clear to this extent on the Saturday, and that only three were clear completely on the Monday and five others do«ni to a trace, while the average reaction Idl to twu third* ut it* prevtoua value At thi* iwrfxl in our invr^tigationt wc luid not yet rcahiictl how eaitily upcciineum might be accidentally cuutanunatcd i( pa**ad at the lact(^ doaets, and *o there may have t>ecn a certain number o( contaminated •pecimen* amongst the*« which would raitc both average*. lUected. Lach girl I to ...llc^l MU -.J-vM Tahle II. A lortnight later a (econd Mrt ul sample* wa« i given two bottle* with her name on tli' tii .t!i t .iik' a* *o CTOBER dTH. 1916. HMeliOB. r... .^f^i'r IL-I r ,^r/«,«J. 40 H-S 1 2\ 0-5 5 1 25 2 US s ■_• II .S 26 2 1 4 •i o 5 1 5 28 6 2 5 29 1 0-5 7 1 1 30 2 8 2 1 31 1 0-5 9 OS i)-5 32 1 lo o i If S 33 M 1 1 \2 ! 1) 35 w II 13 1 ■M It 1 37 0-5 0-5 I.S u-.S 38 Iti i\ > 39 0-5 17 1 0-5 40 l« ;{ 1 41 0-5 u IV» .1 Ij (1 20 ■- ■; £1 •.'3 OWrr.W/orw( Thor and oulv tlic SatuiiU) and 1 •urltcu . ii the MumUy. ice only on the Saturday and •e\-cntern had Tamjc III. A FOOR I>AV«' MtltCITIOK W.i a va m , ; - . . . to lutc;;A)l> ui («a£tiu(t. (Bri«l-rBlMO) Uu Um >Uy oi (Gluta aitd Hm totu «Uy»° f«at C 85 urinary samples were obtained from as many girls ; these showed Webster reactions as follows : — Nos. Reactions. 62 Free 10 Trace 10 1 1 2 2 3 Thus there is only an appreciable amount of T.N.T. in the system in 3 out of 85 girls. This is a most remarkable clearance for a four days' rest, and quite eclipses anything given by alternation of labour (see below). Our returns show that in the course of our routine examinations we had happened to get specimens from 59 out of the above 85 girls on one, two or three days before the holidays. These are given for contrast with the above figures, as follows : — Nos. Reactions. None Free 2 Trace 13 1 19 2 15 3 9 4 1 Intense The explanation probably lies in the complete " cut-off " from all contact during the four days. On an ordinary week-end the girls live in the same rooms to which they have conveyed T.N.T. on their clothing, they are touching it on their clothing, and probably a good many sleep in day underclothing. A very large number of these girls come to lodgings from homes in healtlw situations at a distance, and we know they nearly all went back home for the holiday. They probably all cleaned up smartly and went into gala clothes for the occasion, and also probably enjoyed themselves a good deal in the open air in fresh seaside and country breezes. The effects aie even more striking than the crude comparison of the two sets of figures show ; for of the 23 positives out of 85 after the holidays, 8 (wliich included one of the two reaction of 3 and the only reaction of 2) were passed after the girls had been several hours back at work. The other reaction 3 after two hours back at work, and 7 others were taken during the first day's work. Thus at least 16 of these 23 positives were taken after restarting work. This leaves the position that out of 69 specimens taken before resuming work after the four days' holiday only 2 showed any T.N.T. reaction, and these were " traces." Tables IV, V, and VI. Effects of Fortnightly Alternation of Labour on Amounts of t.n.t. in the system as indicated by urinary reaction. Carried out at National Shell Filling Factory, Urines were obtained from 76 girls " on " T.N.T. and 76 girls " off," with the object of using the urine test for T.N.T. as an indication as to how far freedom from contact with the poison was realised by alternation. All the samples were morning urines, since most or all of the T.N.T. inhaled or swallowed the previous day while at work will have been eliminated by the morning. Thus the reactions give a rough indication of the relative quantities absorbed by the skin of the individuals concerned. The specimens were obtained from 45 girls in the filling sheds (amatol) and from 31 trolle3-ing in the same part of the factory, all having been a fortnight " on " and " off " T.N.T. respectively. On the exploder-bag side of the factory urines were obtained from 31 girls filling (pure T.N.T. powder) and from 14 cleaning, and 31 at " fuses and gaines," the two latter being " off " jobs; all these had been one ' jikI " t>tl " TNT rMpectivoly A (umiiury o< the results > u litiuwii in th« lulluwtng tw 1 1(4 • 1 15 ! I* Tr. Ilpying it?6 o n 13 Thr^ r»^iilt< h|. lit (rom alternation, but thoy also "^ti '"^ • nng "off" periods is not so ah«.ili' 1 1 .-s (or more) of TNT in the uriu' -81 per cent, of trollcycrs. 43 |M:r cuul. u( «.W.iiii:i3, -IH \>i:t i.viii. •>( workers on fuses; confirming other obaervatious on the possibihtics of contact of the trollcyers wiih TNT At I ' were token a rinicnt were in lortu: the li! next table. ilmtated in the I'rinrn <•( I i fortnuTlifi t- the end of the Ms troUeying. These results are instructive, and seem to indicate that those who gave tlie liigh reactions when filUng are those whose skin most readily absorbs T.N.T., and who are therefore presumably the most likely to suffer from poisoning. It may be that they are simply the most careless individuals, but the well-known fact that some of the fatal cases have been those who have rigorously followed all the hygienic rules seems to negative this suggestion. APPENDIX B. Analyses of Factory Air for Dust and Fumic r.v Ixtkaction Apparatus. The apparatus and mode of using it have been described in the text. The connections will be imderstood from the accompanj'ing sketch (see Experiment V). The only portion which varied was the piece at the inlet for absorbing the dust and fume. In the first experiment this was a modified U tube with an expanded chamber to facilitate bubbling on the outlet limb ; this apparatus was very fragile and was broken when in use for the second time. It was then replaced by the two ordinary (J tubes in series, as described in the text, care being taken to test for complete absorption at the end with alcoholic potash, and these ser\-cd lor Experi- ments II, III, and IV. For Experiment V the Young's Fractional Distillation Column, which happened to be available to us, was used for the bubbling and proved most effective for the purpose. Experiment I, September ird, 1916. — Breaking Doivn Home at . — Tliis experiment is really given as a control to the others to indicate that if there were a large amount of T.N.T. dust in the air the apparatus as arranged would absorb and show it. The inlet was placed near a receiving bin at the foot of a leaky shoot where there was abundance of visible dust. No worker in the room would breathe as much as this, but this defect made the room about the dustiest we have seen in any T.N.T. factory. All the workers in this room wore respirators for comfort's sake, but there had never been any cases of toxic jaundice amongst them, nor any excess of minor T.N.T. illness. Their work was mechanical and did not involve much handhng. A volume of 1,633 litres of air was drawn through in twenty minutes. The total solid in the water at the end was dried and weighed and found to be 0-18 gramme ; from this was extracted by weighing 0-05 gramme of T.N.T. In the mouthpiece there was dust weighing 0-26 gramme, calculated by the above ratios to contain ^5 of T.N.T. or 0-07 gramme of T.N.T. So that 1,633 litres of air at this point contained 0-05 + 0-07 giamme = 0-12 gramme of T.N.T. Tidal air of adult man at rest = 0-3 X 18 litres per minute = 324 litres per hour. Add 50 per cent, for exercise and air breathed per hour = 486 litres. So that air breathed in lOJ hours' shift = 5,103 litres. And from above determination of amount of T.N.T. in air the maximum amount of T.N.T. breathed by a worker who had his mouth opposite tliis leak in the 5103 shoot would be = 0'12 x , j^. «= 0-37 gramme. No worker was in this situation, and this preliminary experiment only serves to show that the apparatus will show dust when present. Experiment II, September 20th, 1916.— A'o. 2 Shop, F.— Four girls in shed pressing amatol blocks. A fatal T.N.T. case had occurred in this *!ieiiix 1)1 powder, and e()uaUy cxp<««d to dtut. A voliini.- i>r SStt litres vrx* drawn t)ir<>ut;h. tl»c water was ilrf ! • r. anil tin- w. i>;lii I I'ltjl «5 gramiiio tlu- am-iunt <•( T NT in tliui. a^ * . 12 29 the anu>unt ^4 V N T in 550 litre* ol air waa 0-0021 erainme Volume nl air lireathed in one hour, ieo calculatiMii in Kx()criment 1 (above) > AW^ Volumr »\ ;nf III 7| hour*" «hi(t -=• 7| Thereliiriv luiniiiium amount ol T.N.T. 364S al«tirl»al>l.- \i»m the air « 0-0021 X ,^ -■=' 0-OU iframme Eifttttnent III. Stptettdxr 2\il. I9lfi -Same Shed at Exptnmtnl II — A volume III :{.87ti litres drawn through in one liotir Innu 12 niHJii till I p m. Weight ..( ilrv wilid in water =• 0-O29 gramme Iroiu till*. T NT extrai ted by ether. filtcreil, ev.iporated. weighed •" 0-012 gram. .\ir c.ili-iilated as in Hx|)eriment II, breithe I in 7| h lurs ^ 3.A43 litres Thcredire. iniximuni amount of TNT. '1645 available fur abtiorption from air ^ 0-012 x *^ " — 0-012 gramme EMf .. 7 ^y> > t 8;«« wa-> • .1 I he lonRr- •-r\.kl. \V..K >... ,.,...,.. .,.„. ,„ ,, ,1,.-, ,. .;,..., I-.,- The proi. .rlion <>i T N T. in thi.s was '". 2y •o that the amount of T.X.T. in the dust ol S.iHKi Utres - 0-018 gramme Vi>luiiii- ol air lireathed during 7| hour*' shilt .1 Al.^ Iiirrt Therelore. maximum amount of T N i available trom air dnnng a *hift The average maximum uptake from .^" mrnls II. Ill and IV. is r^l.r.'f r.- tl m' '■Ir' U ■■. . 1' .Vi »n atntnlioiK appar-ttiis. . . ;>~; tn.; I i «.-t .( |.:1! . ..•; I .i it^xti-nAl distillatioti apiMratiM contaimng water, and then through a m«Aiiion:>. Thu appendix (how* in comparativs (oriii the p»rall<-lti>in between thrcr -^ti of oVcrv-nfiirif (l( thf imonfit «l TNT ali-^T»>^! irum the wof !. ' ' ' . - . ■ .. .V . .1 j^ijj o( lo ally W<;«;|iiiig aMay Uuiu tiiu Mu:l>.^l.v/^. pe sets of resulu arc concordant, and to lorm lo T.N.T. in the air (i( tlic Khcdx in thr amount vr, Aa shown by Ex{>criincnt!> II and III <>( T.N r. jU'bji jjHou. The results were as (ollows : Reactions in T. A Tine of DoMC*. Oct 18th 5 |. m. (at tM). 10 mg. All J. IS p.m. .. Oct. iStb— At 7 p.in.. nil : 8 p.m . (.t. ; 9 p.m., I ; 10 p.m.. I-. 11 p.m.. 1-. Oct. I9tb— 12.45 a m.. t. ; a 45 a.m.. ft. Oct. 19th-n.l5 a.m., ml; 7 l» p.m . I-; 8 20 p.m . I : 10 IS p.m.. nil. Oct. 20th— 8 30 am., ml (before tl.iMi < K '. Jist ij :<rc .Vo<«j.— Obaervc that the rr.i M.\ hour* alter Uking the done. *n l tlut thr w^inn i. umjaIIv (Wat witlun twelve hour*. It IS to be noted in the caa« o( B. M. and M. G. F that 72 work accompanied by mouth and nose absorption in small amount went on until 10 p.m. each d;iy, and that the morning urine is a mixed sample of a secretion period from midnight till about 8 a.m. The most important sample in their cases to observe is accorcUngly that immediately before resuming work at 2 p.m. daily. These figures run for B. M. as follows : — Thurs., v.f.t. ; Fri., v.f.t. ; Sat., 1 ; Sun., f.t. For M. G. F. the corres- ponding intensities are — Thurs., nil ; Fri., nil ; Sat., f.t. ; Sun., nil. Thus, with the exception of B. M. on the Saturday, the urine was practically clear each day before resuming work. III. — At the same period B. M. and M. G. F., with their hands com- pletely protected, but wearing no respirators to stop absorption of any T.N.T. in the air, carried on the ordinary work of the workshop. The results were as follows : — Reactions in B. M. Dat«. Period of working. Reaction, and time of taking it. Mon., Oct 16th 2-10 p.m. Oct. 16th— 8 a.m., nil ; 5.45 p.m., v.f.t. ; 11.50 p.m., 1. Oct. 17th— 8 a.m., 1-; 1 p.m., f.t. Tues. 17th Breakdown No work done. Wed., 18th 4-10 p.m. Oct. 18th— 8 a.m., 1- (?) ; 3 p.m., v.f.t. Thurs 19th 2-10 p.m. Oct. 19th — 1 a.m., 1 ; 8 a.m., 1 ; 1 p.m., v.f.t.; 5.30 p.m., t. ; 10 p.m., 1-; midnight, 1 -. Fri., 20th 2-10 p.m. Oct. 20th— 8 a.m., 1 ; 1 p.m., t. ; 1.40 p.m., v.f.t. ; 5.30 p.m., f.t. ; 10.30 p.m., 1-. Sat., 21st 2-10 p.m. Oct. 21st— 4 a.m., 1 -f ; 9 a.m., 1 ; 2 p.m.,1; 5.30 p.m., f.t. ; 1 1.30p.m., 1 -. Sun., 22nd No work Oct. 22nd— 8.30 a.m., 1-; 3 p.m., f.t. Reactions in M. G. F. Date. Period of working. Reaction, and time of taking it. Mon., Oct 16th 2-10 p.m. Oct. 16th — 8 a.m., nil ; 5.45 p.m., nil ; 11 p.m., t. Tues., ,, 17th Breakdown No work done. Wed., „ 18th 4-10 p.m. Oct. 18th— 11.45 p.m., t. Thurs.. „ 19th 2-10 p.m. Oct. 19th— 9 a.m., 1 ; 1 p.m., nil ; 5.30 p.m., v.f.t. ; 11 p.m., 1. Fri., 20th 2-10 p.m. Oct. 20th— 9 a.m., 1 ; 12.30 p.m., nU ; 1.30 p.m., nil ; 5.30 p.m., v.f.t. ; 10.30 p.m., 1. Sat., 21st 2-10 p.m. Oct. 21st — 9 a.m., 1-; 1 p.m., f.t.; 11.45 p.m., ft. Sun., 22nd No work Oct. 22nd— 8.45 a.m., 1- ; 4 p.m., nil. Mon., ., 23rd No work Oct. ^3rd— 10.30 a.m., nil. Tues., „ 24th No work Oct. 24th— 9 a.m., nU. Notes. — The contractions mean as follows : — v.f.t., very faint trace ; f.t., faint trace ; t., trace. Allowing for breaks for tea and undressing, the working period was about seven hours. 71 APPENDIX D. KXFKKIMeNTS ON PrOTKCTIUS OK THE MaHOS. F.xp«nfnenu devised to aflord protection to the slun have be«n camcd out on the lines dcscnbed in tlic text. The reaulti are given in the iuUowinf protocols : — I. — EXPKKIMKWr UPON THE WASHING OP THE MaNOs BV A T.N.T. Solvent iXvlenes). Tlie ftmt column givea the amount of T.N.T. still in the system on returning to TNT work alter a rest penCur« On" T.N.?: XvlMMlo •U this ptnod. T.N.T. work. No X,l«. «Mtun(. IV. "On" T.N.T. No XrUo. 3 Nui» • ■.hmi. 7ih A Sib Jmn.. I»I7. Jan. Ju. Jan. Jan. Jan. Jnn. N.lur« o( Sun. «im1 n. 17. 1«. 19, 11. n. )obm F^'iib. Mun. Th. W. Th. y. 8u. 8. bfMkM.. t. rKb.*u 1911. c. , 1 _ _ F. V It 1 __ 2 G. 3 1 - 2 ft. (fuses) H. (1) .. I 1 3 — I 2 3 f.t. (fuses) 2 H. (2) . . It 1 -_ _ _ __ — . 4 i.,., :: 3 ) 3 ..^ 3 3 3 1 (fOMt) 4 1 t t V.I. V.I. V.I. — t. t. t. R. 2 - 1 .^ — — — — — S. (1) .. 2 1 ^ _ _ S. (2) . . 1 1 1 3 3 1 (btack 3 T.(l) .. T. (2) .. J 1 powder) 2 7 l.t. 3 z W. (1) .. 1 2 — — — — — — — W. (2) .. 1 4 -^ — — — — — — W. (3) .. t. L _ _ __ ..^ _ _ U.W .. — — 1 — 3 1 - — 2 Totrnk .. 19 15 11 13 _ 20 _ IS No. of s«m|>tc-i Ifi II 8 _ 9 __ 8 _ 5 Average intensity 12 14 14 14 — 2-5 "~ 3 Afal«s.— The above Ubie illustrates many points. The Ur«e of bl-illW^ in It -.(n.^i thr ,!irl:, nlltr!« of obtairUntT urin.iri.- v.»-, ■tiirr coti lumn ahow t! fC" .iltrrtvation " The day^ ■ i>n " -show BtMI-rBl»30 The n«e in of the Xvlrn w The column headed III shows the gopd j^esults of the period " oS " T.N.T., but the number of samples is too small for fair judgment ; but Column IV showfs the additive effect of tlie period " on " T.N.T. A large number of controls were carried out upon girls not using the " Xylenes" wash during the actual experiment (Column II, Jan. 11th till Jan. 27th) ; the average of these gave 1 '3, a figure almost identical with that of the girls using the wash — certainly no worse. II. — The Casein-Varnish Experiment. Twelve girls were started on 28th Feb., 1917, with an application of rasein-varnish twice daily to hands and face, before starting work. The results of the urine tests in these twelve, or in as many of them as gave samples, may be summarised as follows : — 28.2.17 I Before varnish and after 2 days on T.N.T. | 10 10.3.17 I After ,, ,, 2 weeks on ,, 10 19.3.17 I ,, „ „ 1 week off ,, 8 30.3.17 j ,, ,, ,, 11 days on ,, 7 28.4.17 I ,, ,, „ 2 weeks on ,, i 6 I i The full table of results is appended. 28/2. 2w?eeon 19/3. 30/3. 2w^^{io„ Number. 2 days on 1 week off lldairBon T.N.T. T.N.T. T.N.T. T.N.T. T.N.T. 1 .. 2 2 v.f.t. 2 .. 1 v.f.t. 1 3 v.f.t. 3 .. f.t. 1 — f.t. 4 .. 2 4 5 .. f.t. 1 f.t. v.f.t. f.t. 6 .. 2 4 3 1 7 .. 8 .. 9 .. 2 1 2 t. 2 2 f.t. _ _ 10 .. 2 2 1 — — 11 .. 1 — — — — 12 .. 1 2 v.f.t. v.f.t. Totals 12 20 9 8 2 Samples 10 10 8 7 6 Average re- action 1-2 2-0 11 11 0-3 The letters f.t. mean faint trace ; v.f.t. very faint trace ; and t. trace. The appearance of the hands and faces of these six girls, who had carefully iised the varnish throughout the period of two months, tallied with the low results in the urinesi The highest of the six is only a " trace." This furnishes another proof of the value of skin protection ; this trace probably represents the amount swallowed. The numbers are, of course, too small to draw final conclusions. Large scale experiments have been arranged at other factories. APPENDIX E fKiM-i-oi.-. jr iMt..i.l».««TS on ADMINISTHa.. .■ ■ OTHER NlTKO-COMPOfNDS IN ANIMAL^ I. — EXPBBIMENTS ON T N.T WITH LeiHAL K. A.—Animatt tltoa'tng Ltvtr Lenom Enfurtrntnt I —May 2nd, l^)lrt —Rabbit »rii;lui:i" given I -5 gram p'Wilered T N T bv mouth at lo dark red colourc (ii«e;t 01 itecrofiis ai> I (at: m centres of lobules. • '.'.O.^O giamaies. Mav 3rd. urine ta arra« caR. Th.^ . louixl .1....! i.ii .\!.4\ lUii , w. P.M. examination thoro was ob lat. p.:.'..r....l ...,,1 ■.t...r ilu.>l launcide showing in »ubcutanr< tlOII The organs were extiucted with hot ' lor TNT with negative results. rnmiiii > ■ *nnuHl I.— May SIh. given by mouth 0-«5 gram ol tlie pink matir.al* or alcoholic v\.i.U No ..(,.., .,. rr .;lts .,-,. M.iv r gr.. tl.'TutHg HO Lt'.tr Li'^tom. 1916 — Rabbit. wciKhing 2.li'2U graronie*. ibtamcd by the action The doic ol 6 gram Idth. nth. 12th. 13th V 12th. -.2^* gmmmrs . ;m M \ "ttl ;.TiiO givr of T.N T. i:i tt.i gram. The dc»e 17th. ?»th. r>th 1916 -RabNt. weighing 2.170 gramme^. . rnt •.•! .'ay 18th), and cont?ired a little free T.K.T. , otherwise no rol-ccaHe ef ccts. Cn this afterncon the urine paF-ed was very dark reddish brcwn in colour, and cr ntained free T.K.T., but no bile, albumen, or blood. On Friday mrrning, Fay IPth, the an-mal was found dead ; thr urine ppFSfd during the night contained a good deal of blood. The P.M. examination was made by Er. Turnbull. The bladder was full of urine, darV: red in colour and c< ntaining blood but no fiee T.K.T. fat this f cried Vcbster's test was not known to us). The tissues were examined ior free T.K.T. by extraction with hot alcohol, but none could be detected. This experiment should be compared with one on T.N.T. residues separated from crude T.N.T. Experiment IV. — May Mth, 1916. — Pabbit, weighing 1,660 grammes, gi-en by mouth 05 gram of " pure " T.N.T. without obvious symptoms. This dosage of 0-5 gram was repeated by mouth on the following dates, th" drug being enclosed in gelatine capsules : — Mav 19th, 22nd, 24th, 26ch, 29th, 31st and June 2nd. This makes in all eight doses of 05 gram repeated at short intervals, totalling 4 grammes. The animal died on Tune 5th. The P.M. examination showed no macroscopic liver lesions. The liver was rather small, and dark brown in colour. The kidneys were somewhat swollen. The urine contained blood and casts, but no free T.N.T. The body weight shows the characteristic decline of repeated doses of these compounds at this- level, as follows: — May 17th, 1,660; May 22nd, 1,670 ; May 29th, 1,320 ; June 5th (dead), 987 grammes. Experimetit V. — May 22vd, 1916. — A small kitten, weighing 500 grammes, was given by mouth 0'5 gram of " pure " T.K.T. The animal died the following day. At the P.M. examination the liver was pale in colour, the Vidneys swollen and injected, and yellow coloured at outer part of cortex, the pleuritic and pericardial fluids were increased in amount and greenish-yellow in colour as if there had been slight icterus present. No free T.N.T. was found in liver, kidneys, urine, brain, bowel contents, stomach contents, or heart muscle. Experiment VI. — May 22nd, 1916. — Another kitten on this date was given by mouth 025 gram of " pure " T.N.T., and on the following day another 0-25 gram of the same drug. This latter dose was vomited up two hours later, and the vomitus contained T.N.T. The animal recovered after being ill, and in the five days after administration its body-weight fell from 530 to 450 grammes. Experiment VII. — May 24th, 1916. — Cat, weighing 2,170 grammes, given by mouth, in gelatine capsules, 1 gram of the pink precipitate of T.N.T. The animal was found dead next morning with rigor mortis established. At the P.M. examination the liver surface was pale over large areas, anl lobulation was very distinct. The stomach contained dark coloured fluid in which the T.N.T. compound was present, and this extended down the small intestine for about 15 inches {i.e. about one- third its length). The kidnevs were swollen and much congested, but the cortex was pale in colour. There was no urine in the bladder, but a small volume passed about one hour after the administration of the T.N.T. gave no reactions for free T.N.T, There was also absence of T.K.T. in liver and kidneys. The lungs were grcNash-brown in the greater part ; pink in smaller areas. This, with the pre\dous experiments, demonstrates that the pink substances formed by the action of T.N.T. on alkalies are • The eipression " pure" T.N.T., as used hero, means T.N.T. eommereially purified. It still contains small percentages of p and y tri-nitro-toluenes, and of the three isomeric di-nitro-toluenes. None of these, however, is approciably more poisonous than tri-nitro-toluene. not lanocuoua, but b*vc abuut the kAOte intensity ol lethal action as T NT. iWll. and hk« xpe mother ititwtanco are more lethal to cats than to rabbitu /:i/Wfi»M«i l7V/—/«iw MM. 1916. -iaM.it, wcitt. ■•■nr%. Tlu» ojiimal wa» givrn. at intervals o< a few lUys. ;i.'; red dmuigcoJO-Sgriira, to try toproUm.ei.hiomccllccts T! ken at intprvaU, counts made o( red bluud corpitfcle*. <»n.i miuun'Mia ol btfinoglobtn percentages, with the following reaulta : — Daw and Utm^f- 'H. ^ W.%bl. Ciramn. 1 - June Mth 1 75-8 7.900.000 i i.sao 2- ,. leth , 75-0 8,400.0O«J — 3.— .. I9lh 4.— .. 2l»t 5.- „ 26th Given 05 gram " pure ' TNT. 58-0 5,200.000 1.310 6.— ., 28th — — 1.350 7.- ., aotb 650 7.400.000 8— July 3rd 650 8.400,000 — 9.- ., 5th . — — — (Urine, red coloured ; 10.— July 6th II.— .. lOth 12.— 18.— 12th t4th Lii'ias tor T.N.T. but contains no 63 , 6.300.000 gram '" pure "J i \ 38 I 4.500.000 bl.»)d ) 1.390 This animal bad the relatively enonnoua weight of six adnunLnterrd in twelve h.ilf-gniro iliwes wittun a period of one month. Note the u.%ual largr drop m IkmIv wriRht. and the rew N'tni; further lnvc^tl^•.ltcd EMfurimuut IX.—Junt \6tk. 1916.- Rabbit, weighing 1,260 gntmiBca. given by mouth, in Rclatine capsules. 2 grammes of the pink prccipitata ol T.N.T. Next day the anim.il lies on its sulc without voluntary move- ments. IS comatose, and lias very feeble respiration Death occurred at 11.45 am. about twenty-four hours after admini.'«tration of the drug. Eif>*rim*nl X -Jttiv I9U. 1916.- KabUt. weighing 1.9rt» gr.immos, ?ven by nuiuth one duso d. A umpl* of bloom the ear at about 3 9U p m itave a faint pouuv* reaction with aKohohc i^..t.v«lurt bat no hh^d 78 The several organs were tested by extracting with hot alcohol and testing for T.N.T. in the alcoholic extract, with the following results : — Liver, negative ; kidney, negative ; heart, negative ; blood, negative ; lungs, a distinct purple reaction of unchanged T.N.T. ; stomach contents, a large amount of unchanged T.N.T. ; brain tissues, negative ; intestinal contents, a little unchanged T.N.T. ; bronchial raucous, reaction of un- changed T.N.T. Experiments on White Rats. — The prolonged experiments (a) in the respiratory chamber and (6) in the workshop over the melting pans, had ehown that air-dust or vapour taken in by mouth and nose had produced no ill results in wliite rats. In the following experiments the " pure " T.N.T. used in the workshops was dusted over the cages or vessels in wliich the animals were kept, so that they trod in it and also doubtless Ucked some off their fur. Experiment I. ^Started March 8th. 1916, ended fatally March \3th. 1916.— Kept a white rat in a large glass Ijeaker, mounted on a layer of felt to keep warm. The beaker was dusted over the bottom with fine " pure " T.N.T. powder. The rat's paws and the abdominal fur, as well as the floor of the beaker showed, in a few hours, the characteristic pink of the reaction given by unaltered T.N.T. with alkaline alcohol. Tliis animal was fed daily in the beaker, and the food was also contaminated with T.N.T. The animal was very ill on March 11th, and was changed over into a clean wooden cage provided with straw. Death occurred on March 13th ; the weight had fallen from 68 grammes at start to 50 grammes at death. At the P.M. examination the. liver looked pale coloured and patchy on the surface. Tlie intestine contained a dark-brown coloured material, looking like altered blood, but giving no haemin test ; no hajmorrhagic areas could be made out. Experiment H. — Started March 8th, moribund and killed March l\th, 1916. — -This animal was fed in a separate chamber so that food did not becomj contaminated with T.N.T., and was then transferred to a beaker which had been dusted over with T.N.T,, as in the previous experiment. On the following day the paws and body were bright pink in colour, and urine passed in the beaker was a bright pink, but it was thought then that this colour might have developed by the urine coming in contact with T.N.T. on the floor of the beaker. Tlie animal was moribund on March 11th (Saturday), and was then killed. The only abnormality found was a brown material in patches on the mucosa of the stomach. The brown was not due to T.N.T., and also did not give the haemin test. Experiments III and IV.— Started March \Qth, ended fatally March 15(A.— A 10 per cent, emulsion of " pure " T.N.T. was made in butter, and this was mixed with bread and fed to two white rats. The animals rapidly fell ill, and both died on March 15th. The P.M. examination showed in both cases dark purple coloured intestinal contents ; these, after boiUng in alcohol, decanting and adding alkaUne alcohol to the alcoholic extract, showed the deep purple colour of the T.N.T. test. The bladder of one contained a quantity of urine which was a bright pink even in the bladder, so proving that the pink colour seen in previous experiments was not due to external contamination but was really formed intra vitam. The livers were abnormally dark in colour, and on extracting with hot alcohol the alcohohc extract gave a markedly strong purple with alkaline alcohol. The same result was obtained with heart-blood, and the tissue of the lungs and brain, and kidney. II. — Experiments with Non-Lethal results, and on Effects OF Respiring Fumes and Dust. A. — Laboratory Experiments on Effects of Breathing Fumes of Crude T.N.T. The animals were placed for these experiments in a respiratory chamber similar in design to that described by Edie, Moore, and Roaf (Bio-chemical 7» Jmim ttie .,t r ■. . .iir drawn o',cf itii- ln-t iu..!t. n IN r lul i.trr:- ' or (umo into the chamlicr which condensed cm tl ExptrtmtHl I AiiguU '.'O/A. 1915 —Two j;,i pectivcly 445 and XSt> ^;I.lIn^ll"). wcrr pUiced in t: lor seven houri d.uly iripiii Monday till I'riilay. t; and left (ree on Siinda>s The exprriniciit w working day^t, and tlicrc wat no observable effect up'n tu- .inun.n'N appeared at the end quite well, ate well, and •difthtly incrcaAed in dunni; the experimrnt. nt which the detaih are AS (filliiw< • — «...ch weight IVn..lm -^ ,^ 1 R«-p.«i..ry J^, Chkiiib-r. '^'■ Fri. .\\.\% 2<>th. I9IS lOa.m,— Sp.u. ,:■.„.. Sat. .. 2Ut .. 10 .. -1 .. Mon. .. 23rd .. 10 ., —5 ,. 5 crammes Tues. 24th ., 10 .. -5 .. 5 grammci We«l , .. 25th ,. 10 .. —5 .. Thuri .. 2«th .. 10 ., —5 .. Fn. .. 27th .. 10 .. -5 .. Sal. .. 28(h .. 10 ., -1 .. Mon. Mn\\ .. 10 .. -5 .. Tues. .. :M»t 10 .. —5 ,. Wed.. Sept IM 10 .. —5 .. Thur, 2nd 10 .. -5 .. Fn. .'. Jr.l " !<• .. --5 . Sat. 4lh Ill 1 Mon. fith ., n> !! 5 ;; Toes.. .. 7lh .. 10 .. — 5 „ . in another t diml and ^'' ATM ry. ha.l : ancr on Thumday. AuRu^t 2«th l im- ..i thcM: ■ in thr clvambcr on Krulay. Si-jitmiltt-r 2nd. ...!. .u'. t It W.1-, vli..«fi tl..it TNT I- I •ling 1 'T''' ■ . . . --• "'K thr c(uU< iwuiia^-ivul i>io.iuvi Hum jbt»»lMli.< .ikutiol Itic multa wrrc Minilar. that i5 to t^\y enlirrly nrfcattvr. th« ammah «hnwrd no trace of injunous action. B -L.tUvdtH »*/ Eftult of BrMlkxn^ Iks Dry l>ful of futt ' r s T A rabbit was daily placed in a l>ux used (or adnuiustennc drap by thr month u> that the head only piojected oat at th* cod o< the boa. 80 A larger box, about 18 inches square at the ends and about 2 feet long, had a round hole made at one side against which the end of the smaller box containing the rabbit might be placed so that the animal's htxid projected in a fairly fixed position into the large box. At the opposite side of the large box a pipe led in which was attached to a rotary air fan by means of which a strong current of air could be blown through the pipe into the box. A glass rod was fixed horizontally a few inches from the point of entry of this air inlet, and a thin muslin bag filled with " pure " T.N.T. was hung by a thread so that it touched this glass rod when at rest. When the fan was worked this bag was blown about, and kept knocking incessantly against the glass rod, so shaking out T.N.T. dust. A piece of blotting paper, moistened with alkaline alcohol and lield opposite the hole in the large box, soon became covered over with pink spots where T.N.T. dust had landed upon it. Also, the rabbit's head, after an hour's exposure here, showed dusty all over. A slight corneal inflammation appeared after a week's experimentation, but even at the end of a long period of exposure there was no general T.N.T. effect whatever. Experiment I. — Rabbit weighing 1,670 grammes exposed to T.N.T. dust-box as above described, as follows : — May 23rd, 1916, exposed for one hour (11.55-12.55) ; an exposure of one hour given on May 24th, 25th, 26th and 29th. Again exposures made of one hours' duration on May 30th and 31st and June 1st, 2nd, 5th, 6th, 7th, 8th, 14th, 1 5th, 16th, 19th, 20th, 21st, 22nd, 26th, 27th, 28th, and for two hours on June 29th and two and a half hours on June 30th. The experiment was discontinued at this point on account of keratitis from the dust, and as no general effects appeared to be arising from the exposure. C. — Workshop Experiments on the Effects of Exposing Unprotected Animus to Fume and Dust over melting pans for T.N.T. These experiments were carried out at W. A., and the fume and dust must be regarded as in excess of anything to which workers would be exposed. Experiment I. — Started October 4th, 1915, ended December 6th, 1915. — Four guinea-pigs exposed in two pairs in two T.N.T. melt houses. These animals remained in good health for the whole period of two months. when one died suddenly and the other three were taken ill. These other three also died, although removed to the laboratory, but the P.M. examina- tion showed that death in all four cases was due to an infection of a pneumonic type, and unconnected with T.N.T. poisoning. This epidemic gave us great trouble amongst guinea-pigs all this winter, and also put a stop to several of our prolonged experiments in the laboratory with sub-lethal doses of T.N.T". Fortunately it did not set in until our experiments on exposure to T.N.T. had lasted sufficiently long to .show the points at issue. These four pigs were exposed for eleven hours daily, as described in the text, from October 4th till November 23rd, and taken away to stores at night, the day temperature being about 80°F. On the latter date there being no T.N.T. effects observable, the cages were placed nearer still to the melting pans, and from November 23rd till December 6th the day temperature for eleven hours daily was about 95'^F. No visible result followed, and, as stated, the deaths were due to infection. Experiment Il.Started December 6th. 1915, ended March 20th. 1916.— Four guinea-pigs were exposed lor this period, as described in the preceding experiment. One died of a pneumonic infection on March 20th, 1916, having been quite well until two days pre\'iously. There were no signs at the P.M. examination of T.N.T. poisoning, and no T.N.T. reactions could be obtained from urine or tissues. The other three remained healthy, and one had a healthy progeny. Experiment III.— Started March 22nd, ended June 26th. 1916.— Six young white rats were exposed for tliis period m the same situation and gl «ori.|itt"ii-> The white (ur turned yellow in colour, but the animal* rr-tAi'<<-.| »<»u| h«ilih and grew to a laree tiize. One was lulled and rr- ■' •' t., ......I -..^pt pcrhiipt a very larje ;i 'ncscntery. There waa no 1 lit with expenntrnts on • !.'*, 1916 — 1 . Iv o<;cupied 1 , •!• rrpi»rt • I thy, ail liavo I.. . .i.A.u 11..11I- «-.i. II u.iv . aiM n.ivi- i«en r-i iiiKlit " /' ,:;W> Jim*// or ml !f that ilvt.-'. otef longtr itme luUnals. I tpttttMtnli OH Gunu.. liM6 — I. itrammea, y^ N T . over V ■( l>c given, t. :'•> graimiK each were administered. 1 \ wr 1. ! • in f;i.iiiiiiii-; at inten'ala ttt-, .1 ' ; October 2Hth. -Il> ruU-r I6th. ■A''M : * VMh. Mi) , J' ■ T . tbat ■I Uble t • :ihed in the (eoerml r(>idcmic Kx/trriHMliI /K— >/.t#/*J So:tmt^> Xtt. U>»5. ruJ*^ Dt<*mU* 17tt. 1915 — Guiac«-pif. wwKlanK 440 gramnu at Murt and S25 fx»mmt» tan .■; at end, given 0050 gramme doses, by mouth ; a companion experiment to preceding one. Number of doses, 27 ; total amount, I 35 gramme. Body- weight, in grammes, November 1st, 1915, -14() ; November 9th, 500; November 16th, 459 ; November 23r(l, 500 ; December 2nd, 520 ■ December 13th, 525. No poisonous effects visible, and the animal continued well for some weeks afterward. Experiment V. — Started November \st, 1915, ended December \5th. — Guinea-pig, weighing 340 grammes at start, 360 grammes at end, was given by mouth doses of 0-075 gramme [i.e., half as much again as two animals in Experiments III and IV) of T.N.T. Total number of doses during interval, 21, making a total of 1-575 grammes of T.N.T. Body-weight in grammes : — November 1st, 340 ; November 9th, 295 ; November 16th, 257 ; November 23rd, 290 ; December 2nd, 362 ; December 13th, 360. No visible effects ; died later, January 18th, 1916, from pneumonic infection. Experiment VI. — Started November \st, 1915, ended December IStlt, 1915. — Guinea-pig, weighing 370 grammes at start and 370 grammes at end. Companion experiment to above ; given doses of 075 grammes T.N.T. Total number of doses, 21 ; total weight of T.N.T., 1 -575 gramme. No visible effects ; died of pneumonic infection four weeks later, on January 12th, 1916. B. — Experiments on Rabbits. Experiments I and II. — Started October ]5th, 1915, ended December \7th, 1915. — Two large rabbits were kept during this period at times in meta- bohsm cages, and at times in hutches in animal house, and given frequent doses of 0-100 gramme of T.N.T. by mouth. Rabbit No. 1 weighed at commencement 2,190 grammes, and was given crude commercial T.N.T., while rabbit No. 2 weighed at commencement 2,520 grammes, and was given twice crystallised T.N.T. (re-crystallised from hot absolute alcohol). Rabbit No. 1 (on crude T.N.T.). — Total number of doses of 0100,'gramme of T.N.T. given during experiment, 37, making a total amount of 3-7 grammes. On December 1 7th this animal was given 0-300 gramme of crude T.N.T. by mouth, followed by 5 c.c. of 50 per cent, alcohol, thus making a total of 4 grammes of T.N.T. throughout the experiment. No positive results were obtained as a result of this long continued absorption of crude T.N.T. This rabbit, during the period, had administered to it at least six-fold the amount wliich the average T.N.T. worker could possibly absorb, by mouth and nose, from factory air in a similar period. The following results of weighings at intervals show that the animal throve and increased in weight ; — October 15th, 1915, 2,190 ; October 26th, 2,137 ; November 2nd, 2,160 ; November 16th, 2,110 ; November 23rd, 2,250 ; December 2nd, 2,259 ; December 13th, 2,570 ; January 6th, 1916, 2,350 ; January 24th, 2,450. Rabbit No. 2 (on recrystallised T.N.T.). — Total 'number of doses of 0100 gramme of T.N.T. given during experiment, 37, making a total amount of 3-7 grammes. On December 17th this animal was given a single dose of 03 grammes, which was not followed by any alcohol. The results throughout were negative, as in the companion experiment with the crude drug, and show that at tliis level of dosage the rabbit is immune to T.N.T. and also to any admixed impurities in its commercial production. This is interesting because, in regard to action in the body^ this animal stands nearer to the action in human beings than any of the other animals experimented upon. The bodv-weights of this animal were as follows : — October 15th, 1915. 2,520 ; October 26th, 2,585 ; November 2nd, 2,830 ; November 9th, 2,590 ,- November 16th, 2,590 ; November 23rd, 2,740 : December 13th, 2,970 : January 6th, 1916, 3,120 ; January 24th, 3,180. FxperinuHl III ^Starttd Aufuil 23rd. 1916. dnetmlinued Augusl 28/A. I9lrt This expenmtnt wait instituted to test for «iun atworption in the rabbit A rat' ISO grammes, had tbr .' vrr an arc* ol the 1m mt H ■ II tm. ■< rtoliutulin II .' 8 ' I'll thr iiuislin wan kat •<( olive oil in wUrIi J ;j:i cut. .i( • imr.- ' T N f • .king the amount nl T N' T a[)|.lK t.. the skn. The Ollr.l iK.i.l.u A ■, . ..\.-,..| ir. (,, .■,>!!..• ,.■• : '.Silk (.r -.1111.1 with .\l f.ir TNT. w; by lickini; aii.l ...... ....I. . ...1... .....1.., ,.,„„...„, ,., i„. urine. The annual w.-ui thi-n '.ilxjiiani box to collect urine. A »am|)I<- 'if Kt iiiiirnmij; nt 1 1 n m wi>s |v.-»le coloured and coiit.uii' ' the •• purr • ! . . . so miicli .ll.-. I .., 1 . on Juno llith with . Ihe animal was giv. i; .1 in metalx.liMii l><>.\ t . . .11.-. 1 : .li:..- .1 -.1 l.r,.>. l..it w.is M..l.ntly M.k and v.imit«-.| up thr Krr. ,t.r p..rt . .(thr.l . iM- HO the experiment was discontinued. riif vv.'ii;lit on July 7lh was J.liMt grammes. Ill ExrEHIMK-XTS WITH T.N.T. iMPfRITIES. ANDTMEMoNO- AND DI-XITIIO- ToMPOUNns WIIU 11 ACCOMPANY IT. IS Tlir ...MMiH.IM IKoLLCTS. /.,' M.n ../ / Uiv Ifi/A. I9lfi ! mea givfu l>v tii'.iiili J i;r.vimiies of T N,T tion of cru.l.- I N 1 ,11 \| \ ( .. n,. . be much darker (l.ulv. ami . tbe urine on Mav hnii and N' JiHh and w.i-i liill' I t?. ... ■ , rt>- T ■■ Uy%. T: : m .Uly '■■wlf 84 Experiment II. — June 22nd, 1916, — Rabbit weighing 2,510 grammes given by mouth 1 gramme of di-nitro-tolucnc, viz., tliat fraction melting at 20-25°C. (L. B. H.) ; this remains in small percentage in commercially " pure " T.N.T. The animal showed no injurious effects a fortnight later, its body-weight was 2,020 grammes, and no later results followed. Experiment III.— June 22nd, 1916.— Rabbit weighing 2.010 grammes given by mouth, in gelatine capsules, 1 gram di-nitro-tolucne ; that fraction ' melting at 65°C. (L.B.H.). No ill results followed ; the body- weight on July 7th was 2,020 grammes, and there were no later results. Experiments IV and V. — Started December \4th, 1915, ended January nth, 1916.— Two guinea-pigs were given mono-nitro-toluene by mouth — No. 1 received doses of 5 cc. and No. 2 doses of 1 c.c. Guinea-pig No. 1 was given four doses of 05 c.c. of mono-nitro-toluene on December 14th, 15th, 16th, 17th. No results were observed. The body-weights were December 14th, 390 ; January 6th, 1916, 340 ; January 17th, 1916, 330. Guinea-pig No. 2 was given four doses of 1 c.c. on December 14th, 15th, 16th, 17th. Weights — December 14th, 590; January 6th, 590; January 17th, 620. No ill results. Experiment VI. — Placed three guinea-pigs in respiratory chamber into which air was bubbled through mono-nitro-toluene, which is fluid at atmospheric temperatures. The animals were subjected to the fumes from mono-nitro-toluene from 10 a.m. till 5 p.m. daily on IStli, 16th, 17th and 18th December, 1915, without showing any effects, and were subsequently kept under observation until January 17th, when they succumbed to the universal epidemic of pneumonic infection amongst the guinea-pigs. Thus, the vapour of the fluid mono-nitro-toluene, which occurs as an impurity in crude commercial T.N.T., is as innocuous quantitatively as is T.N.T. vapour itself, and it is onlj' present in the commercial mixture in small amount. The body-weights at start and finish were 400, 250, 370 grammes and 370, 240, 370 grammes respectively. IV. Experiments with Di-nitro-phenol. Experiment I. — May \5th, 1916. — Rabbit weighing 1,780 grammes given by month 1 gram of di-nitro-phenol died the same afternoon, showing strongly marked dyspnoeie convulsions. The urine was stained a deep yellow colour. Experiment II. — May nth, 1916. — Rabbit weighing 1,935 grammes given, at noon, 05 gram of di-nitro-phenol dissolved in water, by mouth. The animal died at 2 p.m. next day. At the P.M. examination the bladder was found distended ; the urine was dark coloured and contained D.N. P. ; there was no bile present, or blood, albumen or dextrose. The kidneys seemed to be swollen, the stomach wall tliick and oedematous, and the intestinal blood-vessels were congested. Experiment III. — May 22nd, 1916. — Rabbit weighing 2,480 grammes was given by mouth 01 gram of di-nitro-phenol, and showed no immediate effects. The dose of 01 gram was repeated on Maj^ 24th, and on May 26th and May 29th doses of 02 gram were given, all these doses being administered by mouth. The animal was found dead on May 30th. No macroscopic lesions were found in any of the "organs. Experiment IV. — Rabbit weighing 1,450 grammes given by subcutaneous injection 01 5 gram of the sodium salt of di-nitro-phenol, dissolved in 3 c.c. of water. The animal died in 30 minutes. Experiment V. — Rabbit weighing 1,160 grammes given hypodermically 05 gram, dissolved in 07 c.c. of water. A second 005 gram dose was given twenty-four hours later, the animal having survived the first dose, and it died forty-five minutes after receiving this second dose. 85 llic amino denvative ol di nitr«<) KraminrH luid applied on a clip|>ed surface of the back a lanolmr cjintnient which had. in the portion used, about 2 gram of di-nitro phenol On the 28tb it was noticed that the coat had been disarranged, and the aniiiul bad licked ofl some of the ointment A second df.se of 2 gram was given, and the coat fixed firmly. The animal survived both do«e«. i:%p(nmrnl IX Julv 'Mil. 1917 labbit nl l.NO graiiimr* had 3 gram of di-nitrophenol applfd to •skin "f Kif k lirkinc wr\^ rsrrfjdly prevented Next day at II ' ''>■ in the rectum had fallen t M examination showed tluit .i not more than 15 Krani . , , .'.u methaenioglobin could I>edetri.trd in tin- bluud. and iiiiiic wl ttir diuK wa« demonstrable in kidneys, liver or IiIcmkI. ICffvrimfnl .\ Au^-ti'.l Jul. I9I7 Kalibit of l.-lOO gramnu's kimii I gram in lanolin ointment on skin. The animal dieecn absorbed, and at the I'M. examination the liver showed a slight nutmeg appearance. rxptrnnfHl XI .AufuU Wtk. 1917 — Rabbit «>f l.20»i grammea given on the skin in Innnlin O 05 prnm nf di nttrn phrni^l with r,r< obvtrn;^ ri-l-NITI»fv VAPMTMAI » * • /•,• ■ r* giVrll lolli. A (Oll.iu •IX .1. The,:, born [■ ' ■ \ 22nd. 2. 35u. Mav J.itU. J. 1 H) . /u.v 7.' 1 !.t .^iiitnal thus completely recovered even with the*.- /'i/wrinun/ // - .Way 31 if. 1916 - Cat v : ,r,;r-> r.vrn b\ nioullt 195 gr.Am of di nitr.> naphthalcnr :;. ''. inpinous effects of any kind wrr'- p<>T<-eived. an'', is five weeks later, the animal * bo«lv- weight wa..i .' tirUmJa AN INITIAL FINE OF 25 CENTS WILL BE ASSESSED FOR FAILURE TO RETURN THIS BOOK ON THE DATE DUE. THE PENALTY WILL INCREASE TO SO CENTS ON THE FOURTH DAY AND TO $1.00 ON THE SEVENTH DAY OVERDUE. ^'tiifMm RECEIVED NDV 7 R VXQk rRCULATIONDEPt 1 tfiOTf 1 19» RECEIVED APT * 7 1QQR CIRCULATION DEPT. 4//n/,;^ LD 21-100m-8,'34 403717 UNIVERSITY OF CAUFORNIA UBRARY