Document xjwK4GmJOL2QmEYoQqZNr3QDG

,1 > INL'USTPfAL HEALTH - hree of them worked in the m. No changes reasonably ^^ppaque dusts were found. V AND CONCLUSIONS y that dusts encountered in f zirconium metal might pro granulomas was investiexposure and by clinical and iluation of selected ernploynalities attributable to zirmd. * Oke Problem of OrickLoet^L in Occupational ^jtyjedicine ? I Trichloroethylene Metaholism and Its Effect on the Nervous System Evaluated as a Means of Hygienic Control made possible by the gracious distance of Stephen M. Shelton, Region I, U. S. Bureau of Mines, McKerahan, Safety Engineer, treat! of Mines. ams were made through the coT. Morrison, of the l'. S. Public 'ortland, Ore. The microscopic e lung of the guinea pigs was Raymond D. Grondahl, Division >gy, University of Orgeon Med- tEFERENCES E,, and Davies, T, A. L.: F.xperii of Radiographic Shadows by Industrial Dusts: 11. Zircon . Indust. Med. 9:70-73, 1952. and Croxton, F, E., Coni1 Bibliography of Unclassified Tient TID 3010, U. S. Atomic on, Technical Information SerTenn., March, 1951. . W. E.; Trabin, B., and Martin, hronic and Topical Toxicity of late. J. Pharmacol & Exper. 84, 1951. a ZDENEK BARDODEJ, Sc.D. I and ' JIRI VYSKOCIL, M.D., Brno, Czechoslovakia 1 ! Trichloroethylene is widely used all over the world as a solvent for fats and other organic compounds. It is employed for degreasing, cleaning, and extracting purposes ;mti recently also as the raw material for organic syntheses. From the technical point ni view it has excellent properties--powerful i advent action and a convenient boiling point iS7C): it is incombustible, is markedly inert chemically, and has also suitable bio logical properties; owing to its remarkable metabolism in the organism, it is not toxic to the liver. Like other volatile "solvents with tar affinity, it is a powerful anesthetic drug :md nerve poison. The toxicology of trichloroethylene has been extensively studied in Europe and \merica: many investigators undertook re-carch on its narcotic and toxic effects from the clinical, hygienic, and toxicological as sets, The acute and chronic toxicity was itudied in animals and man. Inasmuch as the biological effect of every poison is dis played by the mutual reaction between organ ism and toxic agent, considerable research was done by biochemists who were able, iming to the Fujiwara color reaction * given In some halogen compounds with pyridine and alkali, to follow fairly easily the effect Received for publication March 7, 1955. References 1 and 2. of the organism upon trichloroethylene, that is to say, the metabolism of trichloroethylene and the elimination of both trichloroethylene and its products. PART i In 1933 Briining and Schnetka:i found that the urine of persons exposed to tri chloroethylene vapors gives with pyridine and alkali a color reaction like that of tri chloroethylene and suggested the elimination of this hydrocarbon by urine. In 1938 Barrett and Johnston f demonstrated trichloroacetic acid in the urine of dogs narcotized with trichloroethylene. They were unable to explain its origin. Trichloroactic acid was isolated in the form of its piperazine salt. Powell8 brought additional proof of the mat ter by identifying this compound in the urine of persons on whom an operation was per formed under trichloroethylene anesthesia; she also demonstrated the slowness of its elimination and stressed the importance of the Fujiwara color reaction for the check-up of persons exposed to trichloroethylene in their work. With Paykog 7 she followed the curious slow elimination of trichloroacetic acid after intravenous injection of its sodium salt and derived a formula for its blood level. The validity of the formula was confirmed (for the concentrations studied by Powell and I'aykog) by Bardodej and Krivucova % who followed the elimination of trichloro- t References 4 and 5. t Bardodej, Z,, and Krivucova, M.: Unpub lished data. 581 SL 034025 , A. M. A. ARCHIVES OF IS'DUSTRIAL HEAL! II acetic acid in the urine of both person:? to whom chloral hydrate was administered per os and persons given trichloroethylene inhalations. Bardodej, Chlumsky, and Krivti* cova followed trichloroacetic acid eliniination in a case of accidental severe acute trichloroethylene intoxication. The results are illustrated in Graph 1, The deviation from the original exponential slope of the elimination curve after reaching the elimination maximum on the third day (when trichloroacetic acid was still being produced by the organism) is explained by these investigators by suggesting the influence of a mechanism operating with a slower action than that of the simple passage of trichloroacetic acid through the kidney filter--most probably a slow desorption of trichloroacetic acid from proteins. The acid continued being eliminated for about three weeks. Vyskocil jj observed after trichloroethylene ingestion a somewhat slower trichloroacetic acid elimi nation. which he explained by a prolonged trichloroethylene resorption from the gastrointestinal tract, its sluggish metabolism being toned down by the liver filter. Bardodej and Krivucova found that the amount of trichloroacetic acid in the daily urine increased with increased liquid intake. The same, though attenuated, effect was observed after purine diuretics. Pyrazolone antidiurettes increased trichloroacetic acid concentration in urine portions, probably through an increased retrograde resorption of water in the tubuli. According to Ahlmark and Forssman,fi at the most two-thirds of sodium chloroacetate administered to rats is excreted, while in man, according to Powell.7 the quantity is likely to be higher (at least another metabolite of trichloroethylene in the form of trichloroethanol and isolated its glucuronide from dog urine. Conjugation of trichloroethanol with glucuronic acid and elimination of the formed urochloralic acid are rapid. Trichloroethanol was demon strated in the urine of persons exposed m trichloroethylene by Soucek and Vlachovti * and by Bardodej, Chlumsky, and Krivucova.f Increased glucuronide elimination in persons exposed to high trichloroethylene concentrations was observed by Bardodej. Berka, Chalupa, Nesvadba, and Vyskocil These investigators suggested also the probable formation of monochloroacetic acid,12 demonstrated in 1954 chromamgraphically by Soucek and Vlachova,! g 2 Fig. 1.--Urinary excretion of trichloroacetic acid, same year Bardodej and Priva cova> considering the spontaneous decar- boxylation of trichloroacetic acid and its sodium ^ 'n bdi water solutions and urine samples, suggested another metabolite- chloroform, occurring in slight amounts. It is interesting to note that it was Liebreich '* w^ 'n considered chloroform forma tion from chloral hydrate possible and tried two-thirds of the injected amount). In 1949 Butler," who started by studying the metal* >lism of chloral hvdrate,# found ______ _____ " Bardodej, 7. : Clilumskv, J., and Krivucova, M. Severe Acute Trichloroethylene Intoxication in Industry, Casop. lek. cask. 44:1004-1008, 1955. || Vyskocil, and Berka, l.: Trichloroethylene, Praha, Statniho Zdravotnickeho Nakladatelstvi, 1955. 1? Bardodej. Z., and Krivucova, M.: Unpublished data. # References 10 and 11. "Soucek, B,, and Vlachova, D.: Further Tri- chloroethylene Metabolites in Man, Prac. lek 330-332, 19S4. t Bardodej, Z.; Chlumsky, J., and Krivucova, M.: Severe Acute Trichloroethylene Intoxication in Industry, Casop. lek. cesk. 44:1004-1008, 1955. J Soucek. B., and Vlachova, D.: Further Tri chloroethylene Metabolites in Man, Prac. lek. 6:3.U). 332, 1954. Bardodej, Z,, and Krivucova, M.: Contribution to the Question of Further Trichloroethylene Metabolites Which Could Give a Positive Fujiwara Reaction in Urine, Prac. 16k. 7:97-98, 1955. 582 PROBLEM ol- 7 RU HLi >k< 'L ' --erroneously--to explain the hypnotic on that basis. Inasmuch a3 both trichluroao chloralic (trichloroethanolglucti are metabolites of trichloroetln as of chloral hydrate, Btule: thought chloral hvdrate an product in trichloroethylene m the body. But he was unable to it in dogs' blood after trichloroet lation. Failure in this ex pc experienced also by Bardodej cova |j who conducted a similar human urine. Bardodej and Krivucova r did additional substances in urine v give the Fujiwara color reactio: hydrolysis. The ratio of inorga ganic sulfates was not altered aft ethylene inhalation,12 We think the following schen likely explanation of the curioi. ethylene alteration in the body. unable to decide which of tht courses is really taken in the ) formation of the unstable 1,2,2-tr alcohol, the production of which 11 Bardodej, Z., and Krivucova. lished data. If Bardodej, Z., and Krivucova, M. 1 to the Question of Further Trichloro tabolites Which Could Give a Posit Reaction in Urine, Prac. lek. 7:97-98. o O /\ -------------- > (VI*--CHOI------ T --HaO 1 +HiO 1 OI H ' OH 20H | | -H^ --------- HOI................... CHOI H-OH ----------- -I'Hi li-rHOI a HO--H ------- Cflj--OH ( lhl M TRIAL HEALTH ' ] PROBLEM OF TRICHLOROETHYLENE IN OCCUPATIONAL MEDICINE loroetftylene in the and isolated it --erroneously--to explain the action of this probable explanation for the chlorine-atom hypnotic on that hasis. migration. Conjugation of Inasmuch as both trichloroacetic and uro- ronic acid and l urochloic.lic acid chloralic (trichloroethanolglucuronic) acids are metabolites of trichloroethylene as well inol was demon- as of chloral hydrate, Butler " correctly arsons exposed to drought chloral hydrate an intermediate ek and Vlachova msky, and Krivu- product in trichloroethylene metabolism in the body. But he was unable to demonstrate nide elimination in , it in dogs' blood after trichloroethylene inha n trichloroethylene lation. Failure in this experiment was rved by Bardodej, experienced also by Bardodej and Krivu >a, and Vyskocit.** cova 1| who conducted a similar research on uggested also the human urine. monochloroacetic i 1954 chromatoid Vlachova.$ Bardodej and Krivucova ft did not find any i|t additional substances in urine which would J give the Fujiwara color reaction after acid ckketiqh hydrolysis. The ratio of inorganic and or ganic sulfates was not altered after trichloro ethylene inhalation.18 V e think the following schema the most likely explanation of the curious trichloro ethylene alteration in the body. We are still unable to decide which of the suggested i courses is really taken in the body in the formation of the unstable 1,2,2-trichlorovinyl alcohol, the production of which is the most trichloroacetic add*^ ardodij and Krivu- ^ spontaneous decar- A lacetic acid and its :r solutions and urine || Bardodej, Z., and Krivucovi, M.: Unpubliihed data. 1 Bardodej, Z., and Krivucova, M.: Contribution w the Question of Further Trichloroethylene Me tabolites Which Could Give a Positive Fujiwara Reaction in Urine, Prac. lek. 7:97-98, 1955. Study of the quantitative balance of in haled trichloroethylene in man was con ducted by Teisinger and co-workers u and previously in rats by Ahlmark and Forssman.8 Their results coincide in that about half of the inhaled trichloroethylene is re sorbed. According to Soucek. Teisinger, and Pavelkova, 16% of the resorbed trichloro ethylene is converted to trichloroacetic acid. According to the Swedish investigators, the amount is from 6% to 16%. Barrett and Johnston thought that the quantity of re sorbed trichloroethylene converted to tri chloroacetic acid is 5% to 8%, Forssman and Holmquist18 found in rats 1.2% to 4.2% of inhaled trichloroethylene changed into trichloroacetic acid. Bardodej and Krivucova# thought that in high trichloro ethylene concentrations, and with prolonged exposure, the amount of trichloroethylene changed into trichloroacetic acid decreases. The results of serial studies in industry showed the amount of trichloroethylene changed into trichloroacetic acid to be about 5% to 8% of the inhaled quantity.* # Bardodej, Z., and Krivucovi, M.: Exposure Tests: I. Trichloroethylene, Prac. lek. 7:217-220, 1955. Bardodej, Z., and Krivucovi, M.: Trichloro ethylene Hazard in Prague Dry-Cleaning Estab lishments, Cs. hyg. epid. mikrob, immun. 4:90-94, 1955. nother metabolite -- m slight amounts. It tat it was Liehreich 18 o /\ - CCU--CHCl-- d chloroform formaate possible and tried --HjO 1 +HiO i --COj CCU--COOH-----. CHCls rhovi, D.: Further Tris in Man, Prat. lek. OI H l OH -Hi *OH | | -H.0 HiO i.CU-CHCl---- . CCU=CCl-OH- CCU-CH=0- , CCli- CHCOHli nvy, J., anti Krivucovi, ; loroethylene Intoxication' esk. 44:10044008. 195S. CCU=CHCI CCU--CHiOH -H. i hova, D.: Further Tri- , i in Man, Prac. lek. 4:330-, ' ' b H-OH -------- OHl'lj--CHCl--OH------------- - CC1--CH.O--C.HiO.--COOH frivucovi, M, . Contribu- Further Trichloroethylene '** Give a Positive Fujiwar* lek. 7:97-08, 1055. , wl HO--H HiO ------------ Cei*-OB-CHiCI-------- CH.C1-COOH Metabolism of trichloroethylene 583 sl 034027 s ,,JT- , i,, \. . -t i" :> , 7 A. M. A. ARCHIVES OF IXPUSTRIAl. HEAUli Butler9 found in experiments on dogs that the amount of trichloroethanol from inhaled trichloroethylene is larger than that of tri chloroacetic acid. The results were con firmed in man by Soucek and Ylachova.t In following the quantitative change of chloral hydrate in the body, Bardodej and Krivu cova $ found in the urine a 1:2 total molecu lar ratio of trichloroacetic and trichloroethanolglucuronic acids after a single 0.5 gm. dose of chloral hydrate: after higher doses the ratio increased to 1:4. Occupational hazards in industrial plants using trichloroethylene are estimated hv the following hygienic measures: 1. Trichloroethylene vapor determination in the air. This serves to ascertain whether or not the allowed concentration limit has been passed, thus making sure that the decree of the Ministry of Health concerning allowable limiting concentrations of toxic suhstances in working atmospheres has not been broken. 2. Trichloroacetic acid determination in the urine of employees. This is a means of estimating the average trichloroethylene concentration in the atmo'phere. .1. Determination of the so-called organic chlo rides in urine. We deem this theoretically sounder than the trichloroacetic acid determination, as it permits one, when the procedure is properly chosen, to take into account even the trichloroethanol freed from the glucuronide by acid hydrolysis. The pro cedure has one drawback--it is considerably more involved than the simple trichloroacetic acid deter mination hy the Fujiwara color reaction. Procedures under Measures 1 and 2 are currently used in our laboratory in the fol lowing modified forms. TslrUI.CJtlOETHVJ.EXE DETERMINATION IN Atmosphere \ir samples are sucked through two absorption vessels with spiral capillaries or else through a jxirous plate of sintered glass filled with 5 ml. of pyridine At a suction rate of 1 liter per 10 min utes, the intake in the first vessel is practically quantitative (00%). Colorimetric determination is conducted 'immediately after return to the lab oratory. t Soucek, B., and Vlachovi, D.: Further Tri chloroethylene Metabolites in Man, Prac. lek. 6:330-332, 1954. t Bardodej, Z., and Krivucova, M.: Unpub lished data. 584 Reagents.--Pyridine (analytical grade); 0.05 N sodium hydroxide solution. Procedure.---Four milliliters of pyridine with ill, absorbed trichloroethylene is pipetted into a ten tube (or else an aliquot portion of the sample i. made into 4 ml. with pyridine); 1 ml. of 0.05 \ sodium hydroxide is added, shaken, and heated tur 15 minutes in a water bath at 70 C. then tin mixture is cooled with cold water, 1 ml. of pun fled water is added, and colorimetric determination is conducted with use of the blue filter. The pro duced color remains stable for 15 minutes. Trichloroacetic Acid Determination in Uhi m Daily urine samples collected at the end of tits week are taken for analysis. Reagents.---Pyridine (analytical grade) ; 2()',1 sodium hydroxide solution. Procedure.--Two milliliters of urine is pipettnl into a test tube; 5 ml. of 20% sodium hydraxidi solution is added, and the mixture is thoroughly shaken; 10 ml. of pyridine is next added, and tinmixture is again shaken until it is milk turbid; the mixture is then heated for 15 minutes in a wuu-t bath at 70 C, after which it is cooled with r<>i<i water. From the pyridine (upper) layer, 5 ml. ipipetted into another test tube; 2 ml. of purified water is added, mixed, and colorimetric determina tion is conducted with use of the green filter agaimt the empty sample processed like the analyzed tirin' which is replaced with 2 ml. of purified water. The produced color remains stable for 15 minutes. With higher concentrations it is imperative ti> take an aliquot urine sample for the analysis; with very low concentrations the colorimetric determina tion is conducted against a urine sample free ,,( Fujiwara-positive substance and processed like the urine with unknown trichloroacetic acid content. Thus, possible interfering effects of urine pigment are eliminated. The question of trichloroacetic acid con centration ratio in urine and the level of at mospheric trichloroethylene has been studied by several investigators. Frant and WestendorpIs concluded that we may expeel 200 mg, of trichloroacetic acid in urine under a maximum allowable concentration (MAC i, that is to say, 100 ppm (0.53 mg. per liter i Klkins 17 found 160 mg. and less. Bardodej and Krivucova reported that at 0.4 mg. m trichloroethylene in 1 liter of air--which tthe limit concentration in our countryemployees working in such an atmosphere Bardodej, Z., and Krivucova, M.: Exposure Tests: I. Trichloroethylene, Prac, lek. 7:217-22(1. 1955. PROBLEM vi 1 i<: excreted about 14(> acid per liter of urm the 4,S-Iiour working compared with the United States and li the burden of employ, tar as the standard ) Czechoslovakia U. 5 A. I 100 ppr Higher trichloroacin urine in relation v centration in the air Kylin. and Xystrom 500 mg. of trichloroai conducted experitnen posed continuous!v to days only) ; higher rttered in TeisingerC I of Ahlmark and Foi were arrived at undei Bardodej and Kri i thought the different dependent on trichlor in the air. The same derived from the pape dorp.1 Without doubt differences may be n< ene metaholism vvitl causes for that being exogenous (nutrition. In conclusion, we t!| the urine trichloroact to be more than 160 the allowed standard. United States and Q Certainly been overretration of the noxious siderably, even smaller | he regarded as suspic point of view. Evaluation of the tr | by way of determinati in urine has not vet oped in our country; this point should be monograph of Elkins. || Bardodej, Z., and 1 Tests: I. Trkhloroethv (#55. Si SL 034028] 'l.-iL HEALTH PROBLEM OF TRICHLOROETHYLENE LV OCCUPATIONAL MEDICINE I grade) ; 0.05 N i-xcreted about 140 mg. of trichloroacetic acid per liter of urine. Taking into account pyridine with the the 4B-hour working week in our country as ^^ted into a test ^Bthe sa.nple ir mi. of 0.05 N , and heated for 70 L : then the compared with the 40-hour week in the United States and using the Haber relation, the burden of employees is about the same so :ar as the standard MAC is observed: -r, 1 ml. of purltrie determination i filter. The prominutes. iATioK ix Uhin* |i at the end of the 1 d grade); 20% ,j i urine is pipetted xlium hydroxide 1 ire is thoroughly ' <t added, and the 1 milk turbid; the inutes in a water rooted with cold Czechoslovakia ............0.40 x 48=19.20 U. S. A. (100 ppm).,.0.53x40=21.20 Higher trichloroacetic acid concentrations in urine in relation to trichloroethylene con centration in the air are given by Friberg, Kylin, and Nystrom 18 (at 100 ppm 250 to 300 mg. of trichloroacetic acid). The authors conducted experiments on persons not ex ited continuously to trichloroethylene (five lav- only ); higher results were also encounitred in Teisinger's balance u and in reports of Ahhnark and Forssman8 whose results xere arrived at under laboratory conditions. Bardodej and Krivucova j| and Elkins 19 r ) layer, 5 ml. is 2 ml. of purified metric determinareen filter against lie analyzed urine ; rified water. The thought the difference in percentage to be impendent on trichloroethylene concentration m the air. The same relation can partly be derived from the paper of Frant and VVestendorp.1" Without doubt individual quantitative 15 minutes, is imperative to he analysis; with trie determina- , ;ample free of iroccssed like the die add content. - of urine pigment differences may be noticed in trichloroethyl ene metabolism within certain limits, the causes for that being both endogenous and exogenous (nutrition, outdoor activity, etc.). In conclusion, we think that, upon finding die urine trichloroacetic acid concentration a be more than 160 mg. per liter of urine, lie allowed standard, which is valid for the ceric acid con- I ni led States and Czechoslovakia, has most the level of at- certainly been overreached. As the concen as been studied tration of the noxious element may vary con it and Wcsten- siderably, even smaller concentrations should may expect ! regarded as suspicious from the hygienic in urine under ^;n)itit of view. ration (MAC), mg. per liter), Evaluation of the trichloroethylene hazard less. Bardodej a way of determination of volatile chlorides t at 0,4 mg. of air--which is our country-- an atmosphere if ii urine has not yet been sufficiently develin oui' country; information regarding J^liis point should be sought in the excellent monograph of Elkins.19 i, M.: Exposure W-k. 7:217-220,: || Bardodej, Z., and Krivucova, M.: Exposure lints: I. Trichloroethylene, Prac. lik. 7:217-220, i w5 Table 1,--Number of Persons Suffering Damage io Health in Relation to Urine Trichloroacetic Acid Concentration in Urine According to Statistics of Ah/mark and Forssman Average (Theoretical^ Trichloioethylenc Trichloroacetic AciU Concentra- Peraons with Si#q.- Conceotration lo Urine, Mg./L. tloti tn Air, ,1..--Graph U of Intoxica tion, No. SO 0.03 0 40-T3 0.1-0,19 .jO lno 0.2j 100 300 0.u0 Meaddicvaisl eledave The correlation between trichloroacetic acid concentration in urine and the working hazard of employees was studied by several authors. Ahimark and Forssman 20 found very good correlation between the number of symptoms and trichloroacetic acid concen tration in urine of employees (Table 1). Neither Frant and Westendorp 16 nor we 12 were able to confirm these results. How'ever, let us use the statistical tables of Ahimark and Forssman 30 and suppose that under MAC the exposed persons excrete 160 mg. of trichloroacetic acid per liter of urine; let us further suppose that the change in percentage of trichloroacetic acid is inde pendent of trichloroethylene concentration in the air, adopting thus a linear relation (Graph 2). The Table shows dearly that the MAC standards are too liberal. From Graph 2 we may see that the hygienic limit of 20 mg. of trichloroacetic acid determined by Ahimark and Forssman 30 involves the concentration of 0.05 mg. of trichloroethylene per liter of air, this being the highest allowable concen- CCl.CQQH IN URINE ------- 5--------------------1------------ 1 Fig. 2.--Relation between the trichloroethylene content of tltc air and the trichloroacetic arid con tent of urine, 585 % SL 034029 A. M. A. ARCHIVES OF I.XDL'STRIAL HEAL,, tration in the U. S. S. R., according to Bul letin NSP-101.2' But we think that the good correlation ob served by Ahlmark and Forssman 20 between trichloroacetic acid concentration and the working hazard does not warrant a generali zation for purely theoretical reasons. The acute narcotizing effect is given bv the relation where E is the effect and c is the E=F(c) concentration, but in assay of chronic effect on the nervous system, a state typical of tri chloroethylene, we must not lose sight of the time effect (t) of the noxious element and of the Haber relation (c) dt The remarkable sleepiness observed by us in most employees can partly be attributed to the trichloroethanol formed during work with trichloroethylene. In a preceding paper 12 we reported as one of the most characteristic intoxication signs an intolerance toward alcohol. We think that explanation tor this effect, described in the case of other industrial poisons (toluene, calcium cyanamide, and carbon monoxide) as well, may be sought in attenuation of the oxidation systems by trichloroethylene itself and its metabolism fe. g., oxidation of chloral hydrate to trichloroacetic acid If). The response to alcohol in persons work ing with trichloroethylene being similar to that in persons treated with tetraethvlthiuratndisulfide, we suggest that here also acet aldehyde evolved from alcohol exerts its influence, probably upon the acetylcholine mechanism. The alcohol-disulfiram (Anta buse) response may be suppressed by atro pine administration, and this fact is in favor of the suggested mechanism.# Inhibition of tissue respiration leads to increased trichloro ethanol production, the result being increased sleepiness. And we find both these systems, sleepiness and alcohol intolerance, very often ? Bardodej. Z.; Krivucova, M.. and Pokorny, P An Attempt to Find a Biochemical Explanation of Intolerance to Alcohol in Trichloroethylene Intoxication, Prac. Ik. 7:263-267, 1955. # Bardodej, Z.: Krivucova. M., and Skala, J.: Unpublished data. 586 side by side. Intolerance to alcohol eventu ally disappears when work has been discon tinned. Bardodej, Krivucova, and Pokorny * found also that tetracthylthiuramdisultide in creases intoxication signs in experiment;!'; animals after inhalation of trichloroetht lem Liver damage from trichloroethylene \\anot observed in our country, perhaps owin': to the high purity of the product whirl, observes the standard set by the Britid: Pharmacopoeia. The starting materia! for making trichloroethylene may be tetrachlom ethane or other agents. \\ e agree will, F.lkins 19 that liver changes reported by other investigators may be due to these other agents. Trichloroacetic acid in the form of salt ia practically nontoxic substance; the lethal dose (L. I).TM) for the rat is 3 to 5 gm. per kilogram of body weight.8 Morrison 23 givethe lethal dose of sodium monochloroacetatt for the mouse as 165 mg. per kilogram oi body weight. Bardodej, Krivucova. arm Pokorny,f experimenting on dogs, arrived ,v similar relative values. The potential capacity of the organi.-i,, for changing trichloroethylene into trichlum acetic acid seems, therefore, of advantage m the host. Precise biochemical methods for the evalu ation of the systemic effects of trichloroetlul ene exposure are still lacking. We prefer :< maintain systematic atmospheric controls w our industrial plants and to use preventive measures rather than to spend time develop ing new methods of laboratory research. Am case of chronic intoxication which mirii' occur is entrusted to the care of the mu rologists. PART II Several of the biological effects of triclibroethvlene were discussed in the first part m this communication. With some of the vnl,, * Bardodej, Z.: Krivucova, M., and Pokorny, I An Attempt to Find a Biochemical Explanation . Intolerance to Alcohol in Trichloroethylene Intm cation, Prac. lek. 7:263-267, 1955. t Bardodej, Z.; Krivucova, M., and Pokorny, IUnpublished data. FR('/ /./-. tile organic characterized (1 ) the dirn upon nerve ! effect of char the body. ace, and blood-pr, roethylene tin namely, the !: tissue. Dent inhalation hr, immediate cm failure or pri: intoxication pobserved, [n ; teric inchoate intoxication j Upon recover' damage to the had a patient chloroetlivlemtral hemipare-i eral days, and ; bicipital reflex In chronic in upon the nervo tant. Borbelvof chronic trich toxic encephab organic psychic as a toxic Kor> damage to the may be a fleete< and extrapyra: cerebellar vestd eral nervous s\> tion of nerve changes resultii, have been suggt Among eardio Changes of centr: especially a low may be damage; and conduction of angina pectori Besides the n; tion may be, obsei respiratory tract rfiloroethylene v; SL 034030J 41. HEAL Tt I PROBLEM OF TRICHLOROETHYLENE IN OCCUPATIONAL MEDICINE Icohol eventual die organic solvents, acute intoxication is i t>een disconrif characterized by two pathological stages: 11 j the direct effect of the noxious element |iPoko;ny upon nerve tissue (narcosis) and (2) the isulfide effect of changes the substance undergoes in experimental* the body, accompanied often by liver, kidney, hloroethylene.)and blood-production damage. With trichlo meithiylene wasys roethylene the first stage is the most striking, >erhaps owing| namely, the lipid solvent effect upon nervous rodoct whicb|J nssue. Death following trichloroethylene the inhalation has often been described, the material fot< immediate cause of death being respiratory ie tetrachlori feilure or primary cardiac failure. In acute ' agree widfj intoxication psychically abnormal response is irted by other| observed. In psychopathic persons with hys- these otl ieric inclination, the acute trichloroethylene intoxication provokes hysterical reactions, >rm of salt ['pon recovery only some residual signs of :e; the lethal ferriage to the pyramidal system remain. We to 5 gtn. [fed a patient who attempted suicide by tri- rison ** gives; -hloroethvlene inhalation: she suffered cen >chloroacetat<s| tal hemiparesis, which subsided within sev- kilogram ivucovA, an ral days, and after six weeks only a stronger licipital reflex was to be observed.*4 gs, arrived afj In chronic industrial intoxication the effect ipon the nervous system is the most impor he organis: tant. Borhely 25 describes the incipient stage nto trichlorcri it chronic trichloroethylene intoxication as a advantage iDxic encephalosis, a severer stage as an jrganic 'psychic syndrome, and the severest fr the evaltl| ;> toxic Korsakoff psychosis. Next to the richloroethyl. damage to the brain cortex, other systems We prefer nay !>e affected--the vegetative, pyramidal, c controls id extrapyrainidal motor systems, the ;e preventive rebellar vestibular system, and the perjph- ;ime develo; esearch. An; which raigl of the ne 1 nervous system. Diffuse toxic degeneran of nerve tissue and even patch-like tange.s resulting from small vessel spasm ve been suggested. Among cardiovascular changes, vasomotor ts of trichh first part > of the voli anges of central origin were often reported, penally a low blood pressure. The heart nay be damaged by changes in the muscle id conduction disturbances. Several cases <t Pokorrry, Pii | angina pectoris have been reported. Kxptanatioit Besides the narcotic effect, a local irrita ihylem Intc nt may be observed of conjunctivae and the Jlspiratory tract through the influence of tri4 Pokorny, F?mloroethylene vapors; in massive intoxica tion the result may be lung edema. In sev eral cases the lung edema may have been due to phosgene evolving upon contact of trichloroethylene with hot objects, but we observed lung edema in a person who inhaled only pure trichloroethylene. Liquid trichloroethylene leaves burn-like marks on the skin. We think it useless to discuss the contro versial opinions about liver and blood dam age, as well as the selective effect of trichlo roethylene upon the trigeminal nerve, found scattered in the literature; we never observed any of these and consider them isolated, accidental, and interesting rather than typi cal. Interesting observations, with copious references, were published recently in the A. M. A. Archives of Industrial Hygiene and Occupational Medicine by McBirney 28 and by Kleinfeld and Tabershaw.27 Our object has been (a) to ascertain to what degree the clinical picture of chronic trichloroethylene intoxication is dependent upon the concentrations found in the working atmosphere; (i>) to evaluate the Fujiwara reaction for trichloroacetic acid in urine and its relation to the degree of damage; (c) to follow the course of the intoxication parallel with individual exposure intervals, and (d) to find out to what degree the injury after chronic exposure might be reversible. To this purpose we examined 75 persons en gaged in work with trichloroethylene, their exposures varying from half a year up to 25 years; they were employed in different plants in our district,}: Of these 75 persons, 12 worked in dry-cleaning establishments, and 55 were engaged in degreasing metal parts., The atmospheric concentration of tri chloroethylene in these plants varied between 0.028 and 3.4 mg. of trichloroethylene per liter of air. We also followed clinically the health of eight persons who were disabled and out of work for some time. In analyzing the clinical picture of employ ees working with trichloroethylene, we took special notice, first, of the prenarcotic stage, whose intensity is dependent upon the tri- t References 12 and 28. 587 VX'-f , && K 1 -r.'H I, ;;:*U .... , W r* ' P- A* ysf&z A, it. A. ARCHIVES OP IXDUSTRIAL HEAL 111 chloroerhylene concentration in the air, and, second, of the specific toxic effects resulting from exposures of longer duration. The prenarcotic symptoms oftenest en countered were headache, sleepiness, a drunk en feeling, nausea, and tinnitus. Signs of local irritation were cough and lacrimation. At first trichloroethylene acts euphorically, with work being done in a convivial spirit accompanied by song. Later, signs and symptoms of longer dura tion were seen and varied with the amount of trichloroethylene absorbed--evidence of damage to the vegetative nervous function of certain organs; some of these signs and symptoms persisted after quitting. They con sisted of intolerance to heat and sunlight, hot flushes, perspiration, exaggerated heart beat, respiratory difficulties, reddening of the skin after mechanical or heat insults, intolerance to alcohol, and a strongly positive direct der mographism. Respiratory difficulties and palpitations after imbibing alcoholic drinks, cold hands, and direct dermographism were the commonest signs and symptoms. Exam ination of the histamine blood level revealed no abnormalities even after alcohol adminis tration.12 Vegetative disturbances after alcohol in gestion are most likely due to changes in alcohol metabolism.55 But as we found the intolerance toward alcohol dependent not only upon the atmospheric concentration of trichloroethylene but also upon the duration of work, and as it persists after quitting the, job, we believe the mechanism of this dis turbance to be more complex, entailing per haps damage to the diencephalon. In addition to damage to the vegetative nervous system, signs and symptoms of dam age to the rest of the central nervous system are evident--headache, irritability, emotional lability, loss of psychic control, increased uneasiness, easy fatigability both mental and physical, loss of sleep, fine quick tremor and stronger intention tremor, giddiness, shun ning of society, loss of former interests, per sonality changes, emotional distress with weeping, apathy, depression, loss of memory, and anxiety states. We shall refer to these as the neurasthenic syndrome of exogenous origin and degree. Some of these signs and symptoms wenpresent in some persons before their expos nre to trichloroethylene; these persons sin tered the ensuing damage more readily ami to a higher degree than persons who wenhealthy and emotionally stable beforehand. Increased drowsiness was noted in all pa tients: some fell asleep upon return from work and slept through the whole night. Du., continuance of work, even for one day, caused loss of sleep. Several employees interrupted their leave to get some trichloroethylene, without which they were unable to sleep at all. The history of almost 50% of the employ ees absent for an average of one year revealed drug addiction. This fact was verified upon finding trichloroacetic acid in their urine. Neuropsychic balance was examined by a test for active optical attention according to Chalupa 12; the influence of trichloroethylene showed itself by oscillations of the attention, which were different from those of normal persons. Close attention was paid to decreased jmtency, a very common complaint. To deter mine whether the gonads were damaged primarily or whether the central nervousystem was involved, serial neutral 17-ketnsteroid determinations were made, but the decreased values found were not statistical significant. The decreased potency may lie attributed to damage to the central nervoui system, although increased sleepiness may play a part. A rather large percentage of tinwomen suffered disturbances of the menstrual cycle. In examining the peripheral nervous sys tem. we found very often perineuritis, espe cially in the brachial plexus and in the first division of the fifth cranial nerve. Optical nerves were unchanged, but damage to tin function of eye muscles was encountered in two patients. Damage to the pyramidal and extrapyramidal systems was very slight; we saw fleet- 588 PROBLEM (,l IK ing pyramidal ?ympr a history of acute tr tion. Increased axia several person^ lmt 45 years of age. v arteriosclerotic dam could not be ruled < The above-mentio oid determinations > production of adren mal. The Thorn patients after admit epinephrine t Adren: nigs, e. g., a decrea philes not reaching 5 of the persons exan cotropin (25 mg. , eosinophile level wa> Since we regard th administration of ep the function of the hypothalamus-hvpop' normal results note' damage to either tl hypothalamus. Resul epinephrine administ five out ot nine per^ chronic trichloroetln the number of pathi was, on the whole, si Vyskocil found co mal results--59%--i atmosphere contamii oxide after examina following administr These results were I sons working in hot in silicotics. The examination < a polycythemia, in count was above 5,. patients. This may I pensatory response n rather than tcI toxic marrow. However, tocrit, and ervthrot References 29 and Picture in Acute and .Intoxication, Shorn, lek 03^032 ,. , PROBLEM Oh 7 RICHLOROETHYLENE IN OCCUPATIONAL MEDICINE mg pyramidal symptoms in persons who gave a history of acute trichloroethylene intoxica tion. Increased axial reflexes were found in 'iveral persons hut mostly in those above 45 years of age, where the possibility of arteriosclerotic damage to the basal ganglia tould not lie ruled out. The above-mentioned neutral 17-ketosteroid determinations served also to insure the production of adrenal ,V-corticoids as nor mal. The Thom test was done on all patients after administration of 0,3 mg. of rpinephrine (Adrenalin). Pathological find ings, e. g.. a decrease of peripheral eosinophiles not reaching 50%, were noted in 16% of the persons examined. Following corti cotropin (25 mg.) administration, a normal (osinophile level was observed in all persons, since we regard the Thom test after the administration of epinephrine significant for the function of the system--brain cortexiiypothalamus-hypophysis-adrenal cortex, ab normal results noted here must be due to damage to either the brain cortex or the hypothalamus. Results of the Thorn test after fpinephrine administration were abnormal in ive out of nine persons disabled because of dtronic trichloroethylene intoxication. But ihe number of pathological results--16%-- was, on the whole, small. Vyskocil found considerably more abnor mal results--59%--in persons working in an atmosphere contaminated with carbon monuide after examination by the Thom test allowing administration of epinephrine, esc results were 26% in the case of perworking in hot surroundings and 12% silicotics. The examination of other organs revealed polycythemia, in which the erythrocyte :ount was above 5,250,000 in 10% of the tients. This may he explained by a com pensatory response of the organism to anoxia tlwv than to toxic irritation of the bone Trow. However, the hemoglobin, hema tocrit. and ervthrocvte volume and color concentration in all these cases were normal. Leucocyte and differential counts were nor mal in every instance. Current clinical and laboratory tests for the function of the liver, kidney, and gastro intestinal tract failed to reveal any abnormali ties (MacLegal thymol turbidity test, Weltmann and Takata-Ara test). But we found that persons with preexisting liver disturb ances were very susceptible to the effects of trichloroethylene and developed various symptoms of intoxication, because of which they had to discontinue work with trichloro ethylene. Bardodej and Krivucova || found positive urorosein reaction in the urine of 50% of all employees working with trichloro ethylene. The glutathione level was within normal limits. The examination of the cardiovascular system revealed, besides the vasomotor changes already mentioned, bradycardia (below 60 beats per minute) in 26 patients, especially those with longer working history. This may be due to increase of the vagus tone. The same cause may underlie the ori gin of observed supraventricular extrasys tole. Among persons working with trichloro ethylene for a longer time, we found conduction disturbances; in two instances it was the left Tawara branch block, in one a 3:2 Wenckenbach period and shortening of the PQ and WPW. Heart muscle dis turbances were found by electrocardiograph examination in three persons. Very common were complaints of bronchial catarrh and conjunctivitis and of pains in the joints and muscles, receding after a considerable absence from exposure. Direct correlation of any of these signs and symptoms and trichloroethylene exposure was found only in the prenarcotic signs and symptoms which occurred to a greater degree at higher concentrations (Table 2). Correlation with duration of exposure gave statistically significant results (P<0.01), References 29 and 30; Vyskocil, J.; Endocrine fittcrr h Acute and Chronic Carbon Monoxide oxication, Shorn, lek. 88:41-52. 1956. B Bardodej, Z., and KrivucovA, M.: Trichloroethylene Hazard in Prague Dry-Cleaning Establishmeats, Cs. hyg. epid. mikrob. immun. 4:90-94, 1955. 14 H, A. U. A. ARCHIVES OF IXDI'STRIAL HF.ALI li PRUKI.l. Table 2.--Comparison Among Workshops of Damage to Health of Employees Workshop Trichloroethylene Concentration In Air, Mg./L, Persona examined, no............ ............................... ......... A verage age, yr,,.......... ........................................................ Duration of exposure, yr.................................................... Trichloroecetic erld, me. 1................................................... Dry Cleaning 0.10-3.4 12 42 14 140 Heederhe ................................................................................ Sleepiness .............................. ..,............................................. Drunken feeling,,.............................. ..................................... Nemee ................................................................................... . Dizziness and fainting..... ................................................... Tinnitus ..................................................................................... .. -y Lecrlmetlon ............................................................................ . Cough IlTiUttOD......................... .......................................... .. Reddening of skin,,................................................................. "^Intolerance to alcohol..,.,,,,,,,........... ............................. Oetmnd i*oltlvencss of hiiadi........................................ Neuritis ................................ .................................................... .. --^ Tremors ..................................................................................... Sexuel disturljences............. ................................................ Metutrttel dleturbences........................................................... - > Dlddlneee..................................................................................... Dletarbence of elecp............................................................... Fetlgue ....................................................................................... Xeureethenie eyndrotne............................................................ . ---> Severer neurasthenic syndrome with anxiety states.... . 'v Bredycerdie (below 60 heete/mln.)..................................... Conduction disturbance (electrocardiograph)...,.,,.... Heart muscle disturbance (electroeardiograph).............. Bronchitis .................................................................................. Conjunctivitis ......... .................................................. 9 a e 6 5 2 11 6 8 U 6 8 7 2 1 4 10 11 s 2 4 1 1 3 7 75% 00% 50% 50% 41% 10% 92% 50% 06% 92% 60% 25% 58% 20% 50% 33% 89% 92% 25% 10% 39% 8% 8% 2fi% 58% Histamine substances (tdk./100 ,), arith. mean....... . Thom teat In per cent of eosinophils decrease.............. 2.10 75% Degreasing of Metal Part* -- --------- --- --.-- 0.54-0.83 0 028-0 065 I. II. 19 36 44 31 8 1.75 75 32 5 20% 11 58% o 10% 8 10% 6 81% 8 10% 7 37% 11 58% 9 47% 12 08% 3 16% 7 37% 1 5% 7 46% 2 60% 8 42% 5 20% 9 47% 5 26% 1 5% 8 42% 3 16% 1 5% 6 42% 5 26% 24 07% 25 09% 10 2S% 5 14% 8 ri 17% 12 33% 12 33% 10 28% 8 22% 2 5% 12 38% 3 8% 00 7 27% 6 22% 8 22% 04 61% y 25% n% 6 16% l 3% i 3% 10 28% 12 33% 1.96 04% 2.04 64% Absent from Work 8 48 12 5 62^ 1 12*"] 1 12% o0 > 25% 1 12% 2 25% -2> 25% 25%, 3 37%. 5 62%; 6 76% 5 62% 4 50*1 3 37%, 6 75% 7 87% 1 12% 5 62% 2 25% 1 12% 00 3 37% 1 12% 2.15 54% Table 3.--Dependence of Health Damage Upon Length of Exposure Duration of Exposure to Trichloroethylene Persons examined, no.......................................... .................. Aveng* ege, yr.......................................................................... Trichloroacetic acid, mg./l..................................................... Heedecbe ................................................................................... Sleepineu ................................................................................... Drunken feeling.......................................................................... Nausea .......................... .......................................................... Dizziness and fainting................................... .................... . Tlnoltm ....................................................................................... . + Lecrlmetlon ............................................................ ................ Cough Irritation................................ .................................. . , + Reddening ol Ua..................................................................... s. x Intolerance to alcohol...................................... .................. -+- Decrceeed eeneltlveneec of bend*......................................... Neuritis ...................................................................................... x Tremors ...................................... .......................................... Sexual disturbances................................................................ Menstrual disturbanew........................................ ............. . . x Giddiness ..................................................................................... -f Disturbance of sleep.,.......................... ................................. Vetigue ....................................................................................... Neurasthenic syndrome.......................................... . . x Severer neurasthenic syndrome with anxiety states.... . x Bndyeerdl* (below 60 beete/mln.)..................................... Conduction dleturbence (electroeerdlognpb).................. . * Heart muaefe disturbance (electrocardiograph)............. . Bronchitis ..................................................... ............................ Conlunetlvltlx ..................................... ..................................... Histamine substance* (mg./lOO .), arith. mean............ Tborn Met In per rent of eoeinophlle derreeee................ One Veer end Leu 18 92 : 40 14 78% 07% 28% % 1 8% 2 11% 39% 0 98% 3 17% 28% 2 11% 4 22% 1 8% 1 14% 1 9% 4 22% 0 89% 11 01% 3 17% 00 8 17% o o 00 6 28% 5 28% 1.90 84% Two Yeart end Leee 18 83 35 10 55% 12 87% 8 17% 4 22% 0 83% 7 89% 5 28% 7 89% 7 89% 8 17% 2 u% 6 45% 00 00 8 47% 2 11% 4 22% 9 50% 0 38% 00 2 11% 1 8% 1 6% 4 22% 0 89% 2.04 67% Nine Years and Less 19 36 60 10 53% 12 68% 7 37% 7 87% 7 37% 1 5% 10 53% 8 42% 9 47% 12 63% 4 21% 6 31% 6 26% 3 20% 2 56% 7 37% 7 87% 16 79% 6 31% 1 5% 7 37% 1 6% 00 0 31% 6 31% 2.1S 66% Ten Teen and More 20 80 9 45% 9 46% 4 20% 2 16% 7 36% 4 20% 11 55% 10 66% 10 `50% 14 70% $ 40% 10 60% 10 50% 9 45% 10 60% 12 60% 14 76% 3 15% 7 86% 8 40%; 4 20% 2 10% 0 45% 8 40% 2.0 M% Condition of ermptome Betted with + upon length of expoeure u celculeted with X* reeebed ttac ilgnlAcence 0I P < 0.05 end of eymptomt merited with x. the elgnlncence of P < 0.01. 590 with sign.charactergiddinfsj, ety states, turbance i striking! \ eight per.-, a 3-year t exposure < Atiout <> with trie! vasomotor conj unctiv chitis and < system and As to tl excreted tr of injury t find anyth trichloroaci the degree vapors with ination, an< same perso- In perma exception o no trichlon signs of i present. The resul allowed trie! too high, as ethylene act setting the . in workshop tration arou ployees free The preve cation lies v largely upon Hermetic se; ful manipula trichloroethy has many exc use in indust; forget that it Persons v should take iitj.K.l. SL if 034034 PROBLEM OE TRICHLOROETHYLENE IN OCCUPATIONAL MEDICINE wAh signs and symptoms of more permanent character--intolerance to alcohol, shivers, giddiness, neurasthenic syndrome with anxi ety states, bradycardia, and conduction dis turbance in the heart muscle (Table 3). A strikingly severe syndrome was found in eight persons, appearing in one of them after a 3-year exposure and in the rest after an exposure of more than 10 years. Alx>ut one year after a patient quits work with trichloroethylene, the symptoms of vasomotor disturbance, bradycardia, and conjunctivitis tend to disappear, while bron chitis and disturbances of the central nervous system and heart muscle conduction continue. As to the dependence of the amount of excreted trichloroacetic acid upon the degree oi injury to the patient, we were unable to find anything definitive. The amount of trichloroacetic acid in the urine only shows the degree of exposure to trichloroethylene vapors within a short time before the exam ination, and even this relation varies in the same person. In permanently disabled persons, with the exception of drug addicts, we found almost no trichloroacetic acid in the urine, while signs of intoxication were undoubtedly present. The esults of our investigation show the allowed trichloroethylene concentration to be roo high, as upon that threshold trichloro ethylene acts toxically. We should advocate setting the MAC at 0.2 mg. per liter. Only in workshops with trichloroethylene concen tration around 0.05 mg. per liter were em ployees free of the more serious symptoms. past m The prevention of trichloroethylene intoxi cation lies with the engineer and depends largely upon the discipline of the employees. Hermetic sealing of the apparatus and care ful manipulation can prevent the escape of trichloroethylene vapors. Trichloroethylene ,, lias many excellent properties which make its i use in industry desirable, but one must never forget that it is a powerful anesthetic. Persons working with trichloroethylene should take care not to come into direct contact with it (in the liquid form) and should observe hygienic rules, especially in cleaning the apparatus and in opening it, as these points are the source of most acute accidents. The protective influence of outdoor activi ties was found to be statistically significant (F<0.01). Sportsmen used to exercise in the open air suffered less damage to their health, as they were able more effectively to get rid of the noxious vapors by exhalation and to aid their elimination by oxidation. A similar protective influence was found in protein-rich food, which proved to be of statistical significance (P<0.01).11 In seriously affected persons the admin istration of vitamins of the B group (thia mine, lactoflavin, nicotinamide) and of as corbic acid was found helpful. Work with trichloroethylene is unsuitable for persons with any neurologic or cardiac abnormalities, persons psychically unstable, those suffering from hypotension, bronchitis, or undernourishment, alcoholics, pregnant women, and women with menstrual irregu larities. SUMMARY When proper hygienic rules are observed, trichloroethylene appears less dangerous than other solvents. Trichloroethylene is above all a nerve poison. The most important signs and symp toms of chronic intoxication are intolerance to alcohol, tremors, giddiness, neurasthenic syndrome with anxiety states, bradycardia, and conduction disturbances in the heart muscle. We think the highest allowable trichloro ethylene concentration in the air (0.4 mg. per liter for Czechoslovakia, 100 or 200 ppm for U. S. A.) too liberal and advocate a lower ing to 0.2 mg. per liter in Czechoslovakia, better still to 0,05 mg. per liter. We think that the finding of 160 mg. of trichloroacetic acid in a liter of urine indicates that the MAC has been exceeded, and that even lower values do not exclude that possibility. The employees should take care to get sufficient exercise in the open air, as this 59t SL 034035 f Jb>- 'I, E *{ te. 'm v.. w A. M. A ARCH, i n.S OF I.XDCSTKIAL HkAUlU aids exhalation of the noxious vapor and supports oxidation. The. administration of vitamins of the B group and of ascorbic acid has proved useful. Food rich in proteins helps persons threatened with intoxication. Obranska 127. Brno 14 (Dr. Vyskocil). REFERENCES 1. Fujiwara, K.: t)ber eine neue sehr empfindliche Reaktion zur Chloroformnachweis, Sitzungsber. u. Abhandl. naturforsch. Gesellsch. Rostock 6:33-43, 1914. 2. Jensovsky, I.., and Bardodej, Z.: About the Fujiwara Reaction, Prac. lek. 6:301-305, 1954. 3. Rriining, A., and Schnetka, M.: t)ber den Nachweis von Trichlorathylen und andern halogenlialtigen organisehen Losungsmitteln, Arch. Gewerbepath. u. Gewerbehyg. 4:740-747, 1933. 4. Barrett, H. M., and Johnston, J. H.: Fate of Trichloroethylene in Organism, J. Biol. C.hem. 1*7:765-770, 1939. 5. Barrett, H. M.; Cunningham, J. G., and Johnston. J. H.: Study of Fate in the Organism of Some Chlorinated Hydrocarbons, J. Indust. Hyg. & Toxicol. *1:479-490, 1939, 6 Powell, J. F.: Trichloroethylene: Absorp tion. Elimination and Metabolism, Brit. J. Indust. Med. 2:142-145, 1945. 7. Paykog, Z. V'., and Powell, J. F.: Excretion of Sodium Trichloracetate, J. Pharmacol. & Exper. Therap. 85:289-293, 1945. 8. Ahhnark, A., and Forssman, S.: Effect of Trichloroethylene on the Organism, Acta physiol, scandinav. 2*: 326-339, 1951. 9. Butler, T. C.: Metabolic Transformations ofTriehloroethylene, J. Pharmacol. & Exper, Therap. #7:84 92. 1949. Id. Butler, T. C.: Metabolic Fate of Chloral Hydrate, J. Pharmacol. & Exper. Therap. #2:49-58, 1948. 11. Butler, T. C.: Reduction and Oxidation of Chloral Hydrate by Isolated Tissues in Vitro, J. Pharmacol, & Exper. Therap. 85:360-362, 1949. 12 Bardodej, Z.; Berka, I.; Chalupa. B.; Nesvadlia, O.. and Vyskocil, J.: Recent Advances in Our Knowledge of the Effects of Trichloroethylene upon the Health of Workers, Prac. lek. 4:441-467, 1952. 13, Liebtekh, O.: Cber das Verhalten der trichlorersigsauren Salzen und des Chlorals im thierischen Organismus, Ber. deutsch. chem. Gesellsch. 2:269-270, 1869. 14. Soucek, B.; Teisinger, J., and Pavelkova, E.: Absorption and Elimination of Trichloroethylene in Man, Prac. lek, 4:31-41, 1952. 15. Forssman, S., and Holmquist, C. F..: Relation Between Inhaled and Exhaled Trichlorethylene and Trichloracetic Acid Excreted in the Urine of Rats Exposed to Triclilurethylene, Acta pharmacol. et toxicol. #:235-244, 1953. 16. Frant, R., and Westendorp. J.. Medical Con trol on Exposure of Industrial Workers to Tri chloroethylene. Arch. Indust. Hyg. & Occup. Mnl 1:308-318, 1950. 17. Elkins, H. B.: Analyses of Biological Materi als as Indices of Exposure to Organic Solvents, A. M. A. Arch. Indust. Hyg. 5:212-222, 1954. 18. Friberg, L.; Kylin, B., and Nystrom, A.: Toxicities of Trichlorethylene and Tetrachlorethylene and Fujiwara's Pyridine-Alkali Reaction, Acta pharniacol. et toxicol. #:303-312, 1933. 19. Elkins, H. B.: Chemistry of Industrial Toxi cology, New York, John Wiley & Sons, Inc., 1950, p. 143. 20. Ahlmark, A., and Forssman, S.: Evaluating Trichloroethylene Exposures by Urinalyses lor Trichloroacetic Acid, A. M. A. Arch. Indust. Hyg, 2:386-398, 1951. 21. Soviet Decrees on Hygiene in Projection of New Industrial Plants, Bulletin NSP-101-S1, Moscow, 1951. 22. Bardodej, Z.: Highest Allowable Limits (,l Noxious Elements in Atmosphere and Their Appli. cation for Hygienic Expert Opinion, Zdrav. aktml 72:31-38. 1954. 23. Morrison, J. L.: Toxicity of Certain Halogen Substituted Aliphatic Acids for White Mice, J. Pharmal. & Exper. Therap. 86:336-338, 1946, 24. Bock, E., and Vyskocil, J.: Reversible Hcmi paresis in Attempted Suicide with Trichloroethy lene by Inhalation, Lek. listy #: 353-354, 1954. 25. Borbely, F.: Erkennung und Behandlung der oi-gani5cheu Losungsmittelvergiftungen, Bern, Me dizinischer Verlag Hans Huber, 1946. 26. McBirney, R. S.: Trichloroethylene and |)i chloroethylene Poisoning, A. M. A. Arch. Indust Hyg. 10:130-133, 1954. 27. Kleinfeld, M., and Tabershaw, I. R.: Trichloroethylene Toxicity, A. M. A. Arch, lnduxt Hyg. 10:134-141, 1954. 28. Vyskocil, J.: Effect of Work with Trichloro ethylene upon the Central Nervous System, Lek. listy 8:269-271, 1953. 29. Vyskocil, J.: Effect of High Temperatuin upon Endocrine Functions in Brick Layers, Prac. lek. 4:86-90, 1954. 30. Vyskocil, J.: Endocrine Functions in Silicotics, A. M. A. Arch. Indust. Hyg. 8:402-41.1, 1954. 592 2; ),initroort JlppLDl, GORDON S. BATCHE KENNETH C. WALKE and JOSEPH W. ELLIOTT WIIIIIIIMI Hi:,. / ....im:-,:: , The sodium salt (DNOC) has been a variety of purpose been used as a so-c to kill spores during has proved quite eft It has been used aa variety of pests, it serves as an ovicn cide, and locusts. It i in apple orchards a> thinning blossoms. Though the Food tion 1 has set a zeri as a residue on raw a the U. S. Departme insisted on a poiso; formulations of it. fieldmen, and insect country have coinmt one of the safer mat instance, with the . secticides. This rea sharp contrast to i where there have lx among spray operat this material. The deaths each year o\ years is remarkable Received for publicai From the Communic | Health Service, LT. S. I Otion, and Welfare. 03^036 ,