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Tests for the Chronic Toxicity of Propylene Glycol and Triethylene Glycol on Monkeys and Rats by Vapor Inhalation and Oral Administration

Date: 19470000/P
Length: 25 pages
87491763-87491787
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Lemon, H.M.
Lester, W.
Loosli, C.G.
Puck, T.T.
Robertson, O.H.
Wise, H.
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87491386/87491875/Propylene Glycol B43
87491622/87491874/Missing
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87491763/87491787
14817
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PSCI, SCIENTIFIC PUBLICATION
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LIFE SCIENCES LAB 20/LAB FILES
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12 Feb 1999
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EXTR, EXTRA
MARG, MARGINALIA
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Comm on Air Borne Infections
J Pharmacol Exp Ther
Univ of Chicago
US Army Epidemiological Board
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ybp30e00

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`y r4:}:UY 14817 _.Y-cEo' [&43 TE3Td' FOR THE' CHROI!iIC TOXICITY 0 PROPYLE.NE' GLYCOL AND' TRIETIiYLENE GLYCOL ON MONKEYS AND RATS BY VAPOR INHALATIODi' AND ORAL ADMINISTRATION 0. H. ROSERTSON,, CLAY!'1AN(1.LOOSLr, 'I'PIEOa,ORE~T., PUCK, HENRY WISE;,H'ENRY M. LEMON, wrrn WILLIAM LIySTER,,Ja. Ftom ths Drpartment of lYladieine, 6he Douglas Smith Foundation for bfediwa! Rtaeareh and' the Bartiofi' blemorial Fund of lha Univernity of Chicago and'th'e Commission on Air-Borne lfif'ections, U: 8., Army Epidemiolopi cal' Board Received for publication June b„ 1947 since a_ possibki propylc"" 300 mn . the cl'u glyco1 . pressur The finding that vapors of" certain glycols were highly germicidal for air-borne bacteria and vitruses (1-3)' presented the possibility of' employing these eom- pounds for disinfection of'atmospheres occupied by human beings. Of'the two Specific glycols studied most extensively, namely, propylene and triethylene,, the former ! Boiling was known to be essentiallyy non-toxic (4-7) and while acute toxicity tests on triethylene gl>,,col~had likewise shown tlhat very large doses are required to kill' i animals (3-10) the effect of prolonged administration of this glycol had not been ~'ract ' I4aidity determined. Moreover, not withstanding the known inocuousness of propylene i l; when administered by mouth or injected intravenously, it was felt that in : Solnbil: thesbsence ofadequatie tests we could not assume that the inhalatiom of ' thi& glycol woul& be without' deleterious effect on the lung,%. Preliminary intra•`- Color tracheal' injections in the rat of as little as 0s25 cc: of undiluted propylene glyeol caused marked pulmonary irritation, acute ed'ema and later fibrosis and abscess Aah formatim Knalys The very low vapor pressures of propylene glyeol and triethylene glycol at l'ycols are very soluble eratlue (table 2')as well as the fact that both, room tem g p f%,-_ ~ in the bod'y fiuids, made it seem unlikeNy that in the amounts present as vapor in LD&a the air,,enough'glycol could accumulate to, cause i'rritation, of the resp'iratory' iater tract. Nevertheless it was only as, a resultl of prolonged exposure of animals to tulk; atmospheres saturated first with propylene glycol and later with triethylene glycol ouy that this possibility was definitely exclitded! A brief' report on this work was ; Si, made several years ago when the study was still under way (11). The present f Si communication embodies the results of the completed investigation. spray M.TExtwrs Arm xEnsons donet nf'FJIrvrn7s , F'.m.vJinmA Tha Pl'vnnlw mmnlnvrrri in thPaw toxicitv a re16t d'L soou~ i t 1 ith th ti list bl ified t isl fiicti t ific a e . ons n epsts were nur ms er s w me w e snee a e -t /17.-r. n.. r.,x...7..ir~;.~., m.1...e..........~. rr:,....,..e. ..,...R..,7e.. (- 416n rotLnuI vn..nrisu4inn nf'f.hw olvnnl'a warP Pmmnlnural _ Anrinv 4.hpaanrc[!~ ai'th~ exoeriments sntrol 1' T,'he glycol§ueed in this study were,supplied tbrough the kindness of Mr. D. B. Willie,oa ~ as La and Mr,the Carbide,aad Carbonl Chemiasls Corporation. Thie oompanyhae E: IPOgI'e af' ' ' -P%. abor• e." triethylene glycol labelled "Air Sterilization Grad placed on the market a purified W Gl)-C, 82 ~A I %, . T~+~~ ~ ~co L H '2r1
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PROPYLEN7E. AND'TRIETHYI6ENE GIbYCOLS 'thc com- 'orae 16r tWo t~mer IeU on I tq kill .ot been I~pylene that' in of this r intra- e glycol abacesa d~ at aolulble ~Or in , to Fry ~sla to Ifime gl3-col ii a!orlt was 11e prese,nt fleie toxicity li ta6Te 1:11 iAioda for the tesperunents since as time went on refinements in techniques were devel''opedl which made, possible more careful' control'of the experimental conditions. In the first test of' propylene glycol ivapor onrat's,, a DeVilbiss atomizer 18'180 , operated by air under 300 mm. pressure was used ta introduce a very fine spray of propylene glycol intGo the chamber. The droplets produced were sufficiently small` so that enough glycol evaporated to maintain a constantly saturated atmosphere. The airr pressure supply was regulated automatically by clockwork so that glycoll was TABLE' 1 Purity ipecificalione for propylene,and'tribthyknr plycolr iatended f,ar use in aeria!' diaiijaelion SpeciBe:gravity Boiling point Refractive index Acidity Solubility Color Ash, Analysis Odor LID.e when admin- istered by stomach tube in 50%Q,aque+ ous solution rsorxKrs oLYCCr:. 11.0ii70'to 1.0400 at ~TC. Range between 180-210°C., with 90oJa of the material boiling be- l'ow,195'C. 1.4316--1.4335 Nn Bquivalent to not more than 0.093 mg. KUHper gm. eample Completely miscible with water at 20'C., and leaving no insolu- ble residue Not dkrher than 15 on the plati- num num cobalt,seale (12) Not more than 0'A10% by weight By, periodate ~ oxidation (18)', to give at least 98'i0q'o propyl'ene gly,col!by weight. None In rats, 22 cc. per kilogram bodyl weight* TLU1.Y11M; dL71oDL 1.1220 to 111270' at ~C: 275-,310°C. 1.4649-1.4585 ND Equivalent to not more than 0.19 mg., KOH per gm. sample Completely miscible with water at 2l1°C., andileavring no insolit- ble matter Not darker than 30, on platinum , cobalt scale (1'2). Not more than0.010%, by weight Hpdroxyl!value of,22:26-'13.00 by means of acetic: anhydride- pyridine tieet Slight,, or none Inratb; 15-18.0 gm. per kilogram body weightt • Simil'ar valuea'were found by previous workers (4, 5). t Similar values were reported by earlier workers (8, 10). sprayed for 30 minutes out of every hour. This method was eventually aban~ donedi however, because itl was found tQ1be very wasteful of'glycol. In its stead, a regulated drip of liquid glycol onto~ the bare surface of an elt3etric hot plate at about 225°C. was at first substituted. However, this arrangementl was al§o found unsatisfactory as it produced extensive decomposition of the glycol~ (vide infra)',. An arrangementl which worked fairly well for propylene glycol consisted in a sleeve of glass cloth sewed around'the blade of:a knife-type electric heater so as to cover it completel'y. The heater was mounted in a horizontal position above a dish of g/ycoly, into which one end' of the glass cloth wicking dippedl Glyeol was drawn up into the wick by capillary attraction, and on reaching the It
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54 ROBERTSON, LOOSLIyPUCK, WISE, LEMON, LESTER zone near the heater, was vaporized. The current through the heater was regulated so that the decomposition temperature of the giyeol was not exceeded. A fan placed behind the vaporizer distributed the vapor tliroughout the chamber. The vaporization of ttiethylene glycol in these tests was accomplished by a slightly different method, because this compoundl is more sensitive to thermal decomposition. A satisfactory system for producing athnospheres continuously saturated or supersaturated with ~ triethylene glycol was achieved by placing;a shallow dish of the liquid on a hot-plate which was regulatedi to keep the temp- erature of'the glycol at'100"C. A constant levell device attached to a larger reservoir prevented loss of' volume of the liquid in the dish, with consequent rise in temperature. A slnallI el'ectric fanbehind'the vaporizer, dispersed the vapor throughout the test chamber. Tn, the final test where the concentration of triethylene glycol vapor was kept constant by means of' a glycostat (21) this same principle of'vaporization was employed',,except that the vaporizer was en, closed in a metal cylinder at the top of' which a magnetically-controlled butter9y, valve was arranged. The glycostat,,respondfing to the actual concentration of glycol vapor in the air, automatically adjusted the butterfly valve so as continu- ously to maintain the desired vapor concentration. This last method, which operated continuously for ten months provided the mostl precise andi convenient means for producing a controlled vapor coneentratlon,, over~long periods oftime.. A summary of 'the athooospheric conditions which prevailed' in the tests whieh wilL be described'is presented in table 2. Im considering the concentrations of each glycol vapor attainedlin the air, cognizance must be taken af' the variation in the saturation point' with relative humidity (15). In all the experiments where the glycolil'eveli is listed as "continuous supersatiuration," so much excess vapor was introduced that the room was constantly fill'ediwith a dense fog of, condensed glycol dropleta. This condition would represent an amount of glycol, greatly in excess of' that regardedI as desireable for aerial disinfection, under conditions of' human habitation (16)i PROPYLENE GLYCOL . Inhalation of Vapor by Rats. The first tests on the effect of inhalingpropylene glycol vapor were made on white rats. An initial, colony of 30 animals weighing 80 to 90 grams at the beginning of'I the test were divided into two groups -20' test' and 10 controla. The animals were placed in identical chambers 5"lbng; 3"high and 2'6" deep with 5,$'individuals in a cage. The number of rats in each group was increased by birth of young. Breeding was controlled to produce about equal populations in the two groups. The temperature in, the chambers was maintained between 75 and 80°F: by means of a fan blowing on a small radiator through which flowed a controlled stream of'tap water. By using large trays of, CaCls it was found, possible to prevent the relative humidity exceeding a range of 45 to 65 per cent. The rats were fwrdl on a dry meali diet consisting of'corn meal, linseed meal,, easein, powdered alfalfa„powdered!brewers yeast, CaCO, andl hTaCl: Observa- tions during life were made on gain in weigh, color of coat, possible effects or conjunctiva„ these anima;`- propylene g.' Growth 1tc made by av: periods ofti' the growth experiment,, control nndl with tlie bii rapidly tha A'tma zXMrn Propylene g Propylene g Propylene g Triethylene Trietliylenc Triethylene • Calculi , for vapor I, t From c . months %v, to offer fo condition. change in. The rat large l'itte distinguis observed. tuted for coats of t to d'econr , the surf;i, that tlic -
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PROPYUENE~A'ND~~ TRIETEfYGUNE'6LYCOLS, 55 ber: ' by aa tlkrmal usly, placing', a tk temp- M a larger t rise the vapor ion of (21) this .BSen- butterfly tion of astentinu, , which aavenient of time. trste which tions of tuiation in ts where esoeas'vapor ofcond'ensed greatly in aedltions of s conjunctiva, number'of young born and general condition. As sho«•n' in'table 2 these animals.vere maintained'constantly in an atmosphere supersaturated with propylene glycol vapor:. Growlh Rate'. The growth curves of the two sets of'rats shown in figure 1, were made by averag'ing,'the:weights of individitalsnimals observed during equivalent periods'of'time. The «•eigbts of'the young: born in the chambers were added to the growth curve when they reached~the'value at which their'parents'beganthe ezperiment,,e.g. 80 to 90 grams. The weiglits of'only'the male rats (20 inthe control and 19 in the test, group) were plotted since the females varied so much with the birth of young. The'animals in the glycol chamber gained weight more rapidly than, did'the control rats andl the weights of'the former group at 12 TABLE 2 Atmoaphleric eonditiona preuaidinq,ih the qlycol'vapar inTlalatios eaperimenls xs~xt .ecwsr ~e, .ayr,, at cancxsaanor or OLYCd6'x[QOIibO L0\ uscarxww .ors.r cwwtcorruraurwx % . .r:llil.r Propylene glycol Rats 75-80' 4b-85 0.17 -0.38"'. Continuous supereatu. ration Propylene glycol~-. 11Sonker J&-S2: 60-00 0:23: -0.35" About B0c'/o saturation. (.10-.22'mg:[ll) Propylene glycol' Dionkeys 77-s2 " 0.23 -0.35" Continuous' supereatu- ration Triethylene glycol Rats 77-82 46*88 0.0025- .008Y Continuous~ superastu- ration Tfiethylene glycol 14fonkeys 78-82 5t-60 0.0031- .004dt Continuous supersatu- Triethylene glycol IwLonkeys 78-82' b0-00 0.0031- .0046r ration 8'5--78% saturation (OJ0D2-0.003 mg:/1.) • Calculkted on the bssia of'Raoult's]aw, using experimental dhta of Puck and Wise (14'); for vapor pressures of'pure propylene glycol'., t From experimental data of Wise and Puck (15). *hliad pmpyleae djah" weighing '• 4igaups-20 tRst, Aw!4'Mg,8' high im in each group 4 11 paduce about' tui Aambers was . ;ta a small radiator )rmg large trays TQSeedicg a range ~ wI!,, linseed meall, I.W. Ubserva. powible effects op months were about 501 per eent greater than the latter. We have no explanation to, offer for this'diff'erence since, except for the presence of'the glycol vapor,, all conditions were approximately the same in each group. There was no essential change in the weights of'the rats of'either group after twelve months. The rats'in the g)ycol' atmosphere bredI j',ustl as regularly and produced j;ust' aa large litters as didithe eontrolianimalg: The young of~ the two groups were in- distinguishable in appearance and weight-gain. No conjunctival irritation was observed. Atl one period, shortly after the hot plate vaporization was substi tuted for the atomization methodi of' dispersal, a yellowish: discolbration of the coats of'the rats in the;gl}+col chamber was observed. This was found to be due to decomposition of'the glycol by' an excessively high tempemture (220°C.) of, the surface of the hot plate. When the method of, vaporization was changed so that the temperature of the glycol remained below 95°C., the yellow tint of the
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56 ROBERTSON, ~, LOOSLII,. PUCR~, wISE,~. LEatION„ LEBTER'. coat disappeared. All the rats, both glycol-exposed and normal, appearedIto be in good condition at the time they were sacrificedi lwo' deaths occurred. Exatnirwtiom at' Auurpay. After intervals of' time ftom 3: to 18 months as shown in table 3'y the rats were killedwith an intra-peritoneal injection of pento- barbital sodium, Urine aspirat'ed!fromithe bladder showed no abnorlnalp f`indinga 1' 2 3i 4 5 8 7 8 9I IU I I 12 MONTHS OF EXPOSURE TO GLYCOL VAPOR lttla. , l. . 't'iOlilPA84TIVEGaowTH R*TEa oF RATa'.KyPT.. 'riONYINO00aLi IN/1NATHOBPHE$la:SATDEATlD.wIT$ h80.PTLE.VEGL7COI. WAPOB .Nn u BnnLan Gaovr or CoNraoL AartuiLuLa Male rats onlq i'ncluded in thegra ph• nineteen in the test and twenty in the control ~oupe~ Rate about seven weeks old when experiment begun. in either teator control animals. The lungs were fixed witL Zenlter-fotwol' by'the method previously described (17)which consists in clamping,off the aorta, next eompressiowof the ventricles in order to fill the pulmonary vessels, followed by 'application of a, tight' suture around the base of the heart. The fixing, fluid is then'allowed to run into the ttachea under slight pressure. One section through each lbl,eofthc : Ntuxiitnos's heiw. . Lunga. The contrul' rats v, ar purt or a whole evidence of a 1t, small area of, il the ins•olvemen, resolution "s!'• were wiR,h a eil chambers for 8' unintuLs (tablc - in the,2(i rats ki , 'rhe most eo- uccumulation u '-umber of''rats killed in each chamber at successive intervals Glycol ........ C'ontrol.....,. months residet. of cells increuli, occurred' with. peris•asculur a, tion of rutb fn which us most w•hich presunl: the , OcCa.KIUTAtli normal appea• Other Organ and spleen rev bladder or calil exhibited an o rnhaltthiow c test the etTee, 1' In only one Ji:
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PROPYLENE~ AND! TRL'ETHIFLENE. GLY'COL.Sa. 57 to be each lobe of'the lungs was iaken,as well as sccti )ns of liver, kidney and spleen. ! Maximow's' hemotoxylin-eosin-azure stain was emplbyedL aonths as ! Lungs. The gross appearance of the lungs in both the glycul exposed and of'pento- ~ control rats was normal'except imcertain instances in,whieh eonsol'idat•ion,of a ' '' such regions findigP part or a wholelobe was present On examination of n ~''. microscopic, ~ eviiience,of a localizcdlinfectious process was found. T11is varied from a very !' small area of'' intru-ulveolar accumulation of polymorphonuclear leucoarytes to tlie involvement of a' whole lobe. In some cases the llesion was in the process of' il resolution as shown by the'macrtophagie nature ofl the exudate. Sueh, lesions were with a single' exception faundi only ini rats which had been kept in the chambers for 8 months or longor=' and occurred in 25 per cent of the control animals'(tabl;e 4): In,contrast only two lesions ofia similar,nature were foundd in the 2G'rats kept in a, propylene glycol atmosphere for 8 to 18 months. The most common change'ini the lungs was a pervascular and peribronchial ; accumulation of round cells which first began to 3ppear, aafter the end, of 41'to 5' TABLE 3 Exposure of'ralalo prapylcne ptyeal'uapor -foLVtol by the od'the aorta, next verdll; followed by 1Le fixing fluid is .ectibn through i Number of rats killl"d in each chamber at' successive intierv alb Glycol......... Control....... NVMiL1 or YOMiYII or' MX)qf Vad TO 2ElT QQNOISIONS SOTAL MVMa[l 9 •. 7. 9' 10 Ltl_ ~- ~i- lt 13 t7 m or :.x4 ~ , 4 5 I ® 2 0' 8' 3' qi 4 39 2 1! 0 4 3; 7 38 months residence in the chambers. As time went on the size of these "cullars"' oCcells increased and in certain animals became most pronounced. This ehange occurred witltequal fcequency' in both control' and test animals. F'igure2'shoavs perivascular, collars of moderate degree in a 5 months-old' control rat. Examina- tion of' rate from other sources has revealed the same appearance of the lungs which is most pronounced in old aniimale. Except for these cellular changes which presumably indicate the'occurrence of chronic irritation of some kind and the occasional focal' pneumonitis, the lungs of' both groups of rats presented a normal appearance. Other Organs. Eiaamination1 both gross and histological of the kidneys, liver and spleen revealed!no pathological changes. No concretions were found in the bladder or, catices of the kidneys except in one instance, that of a control rat which exhibited an oblong'stone, l cm. long and'' 0iGcm. in diameter in the bladder. } ZnJutlaLion of Fropplene Glytol Vapor by M' 'onkeya: It seemed advisable also to test the effect of' inhalation of glycol vapors on1 monkeys since their upright r'In only one out of'51 rata,,3'tlo 7 months old„was a pulmonary lesion found.
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58 ltOI1h:R:Tt4o\~~„ L0415LI'.,, PUCA~,,, Nt15E, LF,SlON, , LF:ST~BIt~ TABLE 4 t"aunGcr, 1 f' pNlYuorun' p, /rsiunN oacurriny in rulx: both exNoard amd' unexpascd toaAnaBpheres !•oaheruittgU propylctec or lrrelleylt•tre gl.ytod.rayars~ LF~LnI 1 I I Nl'YBBKSIIOW'~ PRB CCNT iMAL Or,T1Yf:' , K.tTS, t'SEOi rOB itiTAL,NL~LBY:K IY4Pt"LYl~~.IYT ~IIOWIN(: YI'L. F.,U OY. KhTp.. xesu.vS . YONABY'Lt:ylONf, ~--- - w~Nldu ~ fnhalaliun ol.propylene glpcol, i('ouu'o1B un i)JtalAtion of propylene + glycol s-t>; ~~ lnh;d)ttii)nof t'riethy;leneglycGl" I' Cuutruls on inhal=ttiotY or ingestion of lriclhg.H+nc glycol, 341 . 44 2 6 ^ In1ud'tttion of.ttroltyleue gly,col. I 13 0 3-7 luhalatinn of trii•ttiylene glycol 25 4 ilt'uutrulk on inliulution or ingestion of l+ I;Ij~'1•ols 13 0 U • This gruup-inalud/vl unintuls considerably older thau those in the propylene gl'}•coll group aud it is probable that lung , lesiona bad: occurred in sume before the exhuritnent began, ~, position would pn: remain in the ltua ceivably be attribt lungs due to the h Forty-five Mae colony of Columl• exposed to propyl Three insulutetd fort t,he:experimen 50 to 60 per cent beramotunted to 1: mesh steel %vire t% three to four »:e: Number of monke. sied in each clt Glycol:........• Carntrol.......... ' Monkeys died. r'tG..2: PItOTOaNACi[Ol1TItS liUNGOF, A CONTROI. R.AT'FIM6iItOKTtiSIOLU Each blbod'vessellis surraund(yd,by a collar uf'cclln (mononuclear) which ul)pearm to be almumt continuuua ulonk the veaeel wall. The rwnnindrr uf 11ie lung architecture is normal. Fiagnificutiun X 125., chambers contai diet consisted ot was added egg-ri violet radiation Propylene gl:• table 2. Sup('r one chamber w: ivas maintaint.Yt. The lengths l is shoNvfir, in tab arrived,, Thes ject:ion of; O.T. tuberculin test' the experimetr tions made on activity and' :: made at the')z s' These monk of' Anatomy, Cu
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PROPY'LENE .A1rtD~ 'rR[F1T8YLENE' oLYaOLB 59 position would provide the optimum opportunity for the condensed glycol to remain im the lungs. The lack of! deleterious effect found in rats could con- eeivablybe attributed'to the more effective elimination ofthis material'from their lungs due to the horizontal position of the air passages (18). Forty-five Macacus Rhesus monkeys were secured i from the tuberculosis-free udk,ny of Columbia Ulniversity' at San Juan+ Puerto Rico'' .nty.nine' were exposedito propylene glycol vapor and sixteen empl'oyed! as contro s. . Three insulated air-conditioned chambers 9'x6.5 x 8 feet high were constructed for the experiment' in which1 temperatures of' 78 to 82°F. and relative humidities lof 50 to 60 per cent were constantly maintained. The air flow through each eham- ber amounted to 13 complete changes of air per hour. The'cages made of heavy 2' mesh steel wire were 36 x 28 x 39 inches high. Sinee the: monkeys' were small!,, three to four were able to live comfortably in, a single cage. The two glycol TABLE 5 Exposure of n+aakays to proplrfene pt'Yaof vapor Number of'monkeys autop- sied in each ahamber« Cont'rol..................,. 1 2 • Rlonkeys died or were sacri8cedist termination of exposure times indicated in table. of Anatomy, Columbia University Medical School. 3' These monkeys were supplied to:us through the kindhess of Dr. Earl T. Engle,, Professor activity andl any abnormal signs or symptoms. Complete blood counts were made at the beginning of the experiment andl again just before they were sacri- the experiment. The animals were weighed at monthly intervala and observa- tions made on the texture and color of, hair and skin, condition of eyes, appetite, tuberculin teste were negative. These two procedures were repeated atl the end'of' arrived. They also were tuberculin-tested by means of the intraeutaneous in- jection ofI O.T. 1+-10@0 into, the sof't' tissue lateral to the eye. A11' x-rays and is showniin table 5. An x-ray of the lungs was made shortly after the monkeys The leng4hs of time the monkeys were kept in the test and control chambers table 2. Supersaturation of the air with glycol vapor was present constantly in one chamber while in the other a concentration of about 60 per cent saturation was maintained. Propylene glycol vapor was dispersed in two, of the chambers as sliown in diet consisted of''oranges, apples, potatoes, bananas, carrots and bread to, which was added egg-nogs containing vitamin; Bx compliex and i cod I liver oil. lwTo ultra- violet radiation was employed. chambers contained 14 and' 15' monkeys respectivvely, and the control' 16i The
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F)U'. HOBEBTSON, LOOSLI„ PUCK„ WISE, LEMON, LESTER fic:ed. Tests for the ability of the kidneys to concentrate urine were conducted at the end'of the period of observatibn. Within the first seven months, three of' the sixteen monkeys in the control chamber and seven of the 29 animals in the glycol chamber diedl Eight other monkeys were sacrificed at the time they were very ill' in order to obtain anti- mortem tissues. The distribution of these deaths and infections is shown inn table 6. The weights of'the two groups of animals are shown in figure 3. Final weighta of sick monkeys just before being sacrificed are not included. Unfortunat;elx,, the weight gains in the twa groups of' monkeys could not be compared for longer than five months due to an insufficient number of'reemaining controls. Except for the period from five to eight months when the monkeys in the gL'yeol cham-. Tl4BLE 6 Occurrence of disaaae and dtath in control' and propylene qlycolsxpored monkeys aafoi: wa¢anufo ao lxlsarl0)r.a01[: ' Nemr rode Bteteti.l nXsm- 1G7nv. C.wa uaEoowa SQTIhc xw.oR a~uras u~a ~rcu la(ae, Inteetiba tep . tritkn and infary tiao -- (3lyeol group(2gianinoi}: DS d 2' 2 l 1 ~ 1 '1 k I 7 ~ e ..................... Sacrifiized when very ill:. 3 ora 2 oral I 1, nown cause un 6 19' Control!group (16 animals) I Died.................... .., 2 l cauae unknown 3 Sacrificed when very ill.. I& 1 ora1i I L,inj,ury 7 6 Tests for pt their ability t bera lost weight (found to be due to insufficient food)athese animale gained weight Faa; at a normal rate until they were sacrificed at twelve months, The results of blood counts and hemoglobin determinations are shown in ~.era e~ table 7. Upon arrival in the laboratory the monkeys were all found to be grams. suffering from a considerable degree of'anemia. That this was probabl'y notl due entirely to the round worm infection (described beloav) is shown by the fact that on a liberal diet containing ample vitamins the blood' picture had improved Btood counr: markedly by the time these animals were sacrif`iced! Restoration of the higher level occurred within three to four months and thereafter the blood picture remained essentially unchanged. The blood of the monkeys maintained in thee glycol atmosphere showedi a slightly greater increase in red blood cells andi a distinctly higher hemoglobin content than did the control animals." Gla col groc • At about the f9th month the quantity of' food was reduced lto the,amount which the ani- med6 would~entirely consume. This was found to be mistaken economy since restoration of ~ Control gr: an excess supplyof' food following the 8th month weighing, resulted in a rapid'and continuous gsin in weight. t~Y « we wish to record our indebtedness to Dr: Leon 0. Jacobson, Department of'Medicine, ~ University of Chicaga„and his laboratory ataff for, carrying out theae red' counts and hemo. water an globia determinations. .~' ~ urine e4F ~'
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e i a F I ce eon uUCted o tfVe contcal Eigtitother obtain antfi- inal weights ~nf crtunately, for longer 4*S pantrols. Eiecept }it6e glycol cham:- W.qawd' mon,t.y. 70 = W 60H z d: W OL V 20'~ IW n r 1 2 3 4 5 6 T 6 9 1Q In ia ttiow ' are shown in vnall found to be ,as probably not due awn by the fact that aure had improved tation of the higher r'the blood picture s maintained in the d' blood cells and a IDals.a' .mount which the ani!- y since restoration of anpidlandcontinuoua rrtment of il2edicine,, red counte and hemo. is shawn in PROPYLENE AND TR7ETHYLIINB DLYCOL& 61 Tests for possible impairment of' kidney function were made by determining their ability to concentrate the urine during,'a period of 24 hours in which both F- M01WTHS' OF EXPOSURE TO GLYCOL VAPOR Fso. 3. Cb>.rsasrrvrs Caowa Iturse orr rifaxaxrs Knra Corrrnvaouszs rN AN Asxosassas SrrasA^raD w mr PaoeTrxNS Gi:cor. VAPOR AND: A.(,'a$oQP. on'(ONTBOL6. Ar•era e inifisl lweights of monlee~!s in glycol group 2959 grams and,in control group 2459 grams., 'The figures in parenthesis indicate number of animals in each weighing. TABLE: 7 Blood' couats and'heraopldbin determimatiuaa of manlacys ezpmaed uD FroBYfs" 'OfYa,'vaP0r ~ ~ DIR01i1RiAL RDa Dr asxie' ' rDUrla~a .: oaD Qria , sL wD '. W:LS sra aw.ui py~w ~d L~" ltana- rtes ~otino- h11n Btra- I pila ur. ~,~ q . . . p p 6lycol group' Initial 2.38 15.9 11.9 58' 27 11 8 1 Finrd ba8 22.3 13.4 , 71 18 7 , 9' 1 Control group Initiali 2.81 18:8 T1.8' 44 29 17 7 1 Binal 4,.77 26L1 11.9 67 17 10 1 1 water and food were withheld. Both groups of monkeys concentrated their urine equally well under these conditions. Microscopic examination of the

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