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'130 . Annals New York Academy of Sciences -<3. Ducois, P., P. Amblard, B. De Bionicourt A I. Leqiuno. 1972. Acropathie polyvinylique professionnelle. Bull. Soc. Franc. Dermatol. Syphiligr. 79s 197. -49. Eckarot, R. E. & R. Hindin. 1973. The health hazards of plastics. J. Occupa tional Med. 15s 80. 30. Eomondson, H. /V. R- I- Pams. H. H. Frankel A S. Borowski. 1967. The early stage of Itver injury in the alcoholics. Medicine 4<t 119. 31. Europaciiemie. 1972. Handelsblatt GmbH. DUsseldorf, West Germany. 52--Sjllbihh t T 1057 Tndimrial. trsxU/Jofty--Ind-xdit-Jh. U/illiumwA-WitHTrr> -Companyr-Ballimote, Md. 33. Filatova, V. S. A E. Sit. Gronsbero. 1957. Sanitamo-gigieniSeskie usloviya truda v proizvodstve polikhlorvinilovoi smolyi 1 meryl ikh ozdorovleniya. Gigiena Sanil. No. 1: 38. S-t. Filatova, V. S,, L. I. Balakhonova St E. Sn. Gronsbero. 1958. GigieniJeskaya kharakieristika proizvodstva khloristovo vinila. Gigiena Truda Prof. Zabolevaniya 2(1): 6. S3. Filatova, V. S.. E. Sit. Gronsbero, N. A. Smirnova, E. A. Stulova St 1. V. Oresckevi&. 1965. Voprosyl glglcnyl iruda I sosioyanU zdorov'ya rabotlkh, zanyaiyikh na proizvouslve lalekinovo polivinilkhlorida. Gigiena Truda Prof. Zabolevaniya 9s 9. 36. Filatova, V. S. Si V. A. Antonyuzjienko. 1971. Gl'gicniteskiye usloviya Iruda i professional'naya zabolevicmosl' rabotikh proizvodstva suspcnzionnOvo potivinilkhlorlda v dinamike za ryad let. Gigiena Truda Prof. Zabolevaniya 15(4): 32. 1 37. Fisciier, J it. Munoschenk A R. Wolf. 1965. Mllzszlniieraphle mil l-Bromor-V."****yi-|Nir. (BMHP). Fortschr. Gebiete Roenlgensirahlen Nuklearmcd. IUj; 349. 38. Fisciier, J., R. Wolf St H. Gamm. 1973. Die Milzszintigraphic. Dlsch. Arzlebl. n No. 7:401. ____ nc.-j [i- -fi.ii-- C s 116a. Tnmnrs nf She livir In nf ihf..Liuv. I. `h-.HIff, Prt 3<a-edii-l. n. fcrpptllVOU Cuiirpauy. Philadelphia, PjT du. uiTSios, C. T. 1971. ,'.ko st'aolyiis In PVC workers. Med. Bull. Stand. Oil Co. 31(1): 49. 61. GOntiier. O. 1956. Die Kunstsioffc und ihre irbeitsmedizinische Bedeulung. Zenir. Arbeiismed. 6i 156. 62. Harris, D. K. 1953. Health problems in the manufacture and use of plastics. Drit. 1. Ind. Med. 10; 255. 63. Harris, D. K. St W. G. F. Adams. 1967. Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. 1. 3t 712. 64. Hbnsciiler, D., Ed. 197271973. Cesundheitsschkdllche Arbeiustoilc. Toxikolo- gisch-arbeiumedtzinische UegrUndungen von MAK-Werten (Maxtmale Arbeitsplatz-Konzentrationen). Verlag Chemie. Weinheim, West Germany. `V 65. Hkrri.e, K. 1963. Polyvinylehlorid. In Ullmanns Encyklopddie der lechnischen Chemie. \V. Foerst. Ed. 3rd edit. Vol. 14. Urban St Schwarzenberg. MUnclien, West Germany. 66. IIervieux St Tessier. 1959. Quclaucs observations d'expositlon el d'intoldrance aux dlrivds vinyliques el aux rlsines dthoxyllques. Aren. Maladies Profess. 10s 4!. 67. Iuer, F. I.. 1970. Portal hypertension In the presence of normal liver morphology. Ann. N.Y. Acad. Set. 110(1): 115. 63. International Larour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. Is 387. 69. International Larour Offici. 1972. Encyclopaedia of Occupational Health and Safely. Geneva. Switzerland. Vol. II: 1467. Irish, D. Oi 1863 Ihl.ngrnatrrl hydrocarbons! 1. Allphatla. 3* Industriat Hygiene -awd-TorlCOiOty. Voli Hi Taxieelegyi Di-W. Fawstt b D. O. Irish,.-Heir fnScx.eeiuiLri'ubl.'zi.v... NvwYuit, 11.7. 71. Javitt, N. B. 1970. Clinical and experimental aspects of sulphobromophthalein ind related compounds. In Progress in Liver Disease. H. Popper St F. Schaffner, Eds. Vol. 117. Grur.e St Stratton. New York, N.Y. 72. luoAii, J. D.. A. E. M. McLean St E. K. McLean. 1970. Biochemical mechanisms of iiver Inju.-v. Am. J. Med. 49i 609. 73. JOiie, 3. & C. . Lange. 1972. Sklerodermleartige HautvcrKndcrungen, Raynaud- Syndrom u.-c /w.-ccsteolysen bel Arbeilern der PVC-hersteilcnden Industrie. D<ui. Med. Wccfcjcrtf. 97t 1922. T002T6fc2 I09Dda Marstcllcr el a/.: Splenomegalic Liver Disease 13V 74. Kelly, R. E. 1973. Vinyl chloride and acroosteolysis. J. Occupational Med. 15; 75. Kl8a5t8s.kin. G. 1969. Toxic and drug induced hepatitis. In Diseases of the Liver. L. Sclsi/T, Ed. 3rd edit. J. B. Lippincotl Company. Philadelphia, Pa. 76. Klinoe, O. & H. W. Altmann. 1971. Morphologic loxischer Hepaioscn. MOncb. Med. Wochschr. 113s 1329. 77. Kluge, T., H. Sommersciiild St A. Flatmark. 1970. Sinusoidal portal hyperten 78. Krsaiomne.rS, uCr.geGry. S6i8Jt .2E94. .Mutchler. 1972. The correlation of clinical and environ mental measurements for workers exposed to vinyl chloride. Am. Ind. Hyg. Assoc. 7. 33: 19. 79. Langu, C.-E-, S. JOtte, G. Stein St G. Veltman. 1974. Die sogenannte Vinyl- chlorid-Krankheit--cine berufsbedingte Sysiemsklcrose? Intern. Arch. Arbeiis 80. med. Leake, 3C2.sD1.. 1934. The role of pharmacology in the development of ideal anes thesia. J. Am. Med. Ajsog. 103; I.__________________________________ 4lli I i-.Tii. n IQKK I T...S1. .1 -ti. .1. |f............ 82. L-WiFlavMR-eG, eMrm. s].m1T972. Internationales Symposion der Werksdrzle der Chcmischcn Industrie, 27-29 April 1972, Ludwigshafcn. As cited in Stein er at., 1973. ------------ -- -- -- ................ tr-----LJ_J----- - j II....: - too 84. Lester, D., L.'a, Greendero A W. R. Adams. ($3.' Effects of single and re peated exposures of humans and rats to vinyl chloridc/Am. Ind. Hyg. Asaoe. 3. 24i2' v--" 64^427 r86. MacSween, R. N. m., J. M. Vetters, S. K. Ross, J. Ferguson, J. M. JohnS' 4 T CiwnienN. 1971. Haemaneio-cruJolhelial sarcoma of Ibe liver. J. Pathol. 109: 39. _________ | In the Producttuii andTTtrersstiiv ur-fujiii-i. E4jo*Ii Pubtiihim Cummin. 88. Maltoni, C., M. Cresfi A P. J. R. Burcsi, Eds. 1973. II International Symposium on Cancer Detection and Prevention, Bologna, April 9-12, 1973. Excerpta Mcdica Ini. Congr. Ser. No. 275. 89. Marin, A., J. Strauss, R. Miciiiels, J. P. Benoit, R. Baltie St C. Pierre. 1967. Acro-ostdolyse d'originc professionnelle (Travail present^ k la Liguc Francaise contre ic Rhumatisme, sdance du 18 janvicr 1967). Rev. Khumat. 34s 340. 90. Markowitz. S. S., C. J. McDonald, W. Fetjiiere St M. S. Kerzner. 1972. Oc cupational acroosleolysis. Arch. Derr 91. Marsteller. H. J., W. K. Lelbacii, ' Roiiner A G. Veltman. 1973. Chn in der PVC-Produktion. Deut. Med. 92. Mastromatteo, E., A. M. Fisher. H halation toxicity of vinyl chloride I I. 5s 394; Bull. Hyg. 36s 244. 91 Mavpm<--------- .969 ITrrnpnllnnaL a^ "''to. jri iie, C-. -E. -Lange, H. G". ^ aerschaden Kbgc>ii AArrbbeeiitleerrnn II. Qianzjger. 1960. Acute In als. Am. Ind. Hyg. Assoc. ams-A-Wilkiiij Cutlip4liy.~'/6oc7 /C. 94. McCord, C. P. 1970. A new occup 12s 234. 95. Mikkelsen, W. P., H. A. Edmonc H 0) sorn. 1. Occupational Med. to s, A. G. ReDEXER A T. B. Reynolds. 1963. Extra- and inn (hepatoporiai sclerosis). Ann. Su H pertension without cirrhosis 96. Misqeld, V.. H. J. Stolfmann 0) Vfnylchlorid-Polymerisate und/ '73. Zur Intoxikalion durch node. Z Haul Geschlechtskr. 48t 425. 97. Morris, J. S., T. Htut St A. E. R Ann. Rheumatic Diseases 31s 3 V . Sea r' erma and portal hypertension. vi i == Q the liver following infection of 98. Nettlesiiif, A. A W. J. Fink. 19 thorotrast. Am. 1. Clin. Pathol VJ 99. Oettel, H. 1963. Gewerbeioxikon-,.. ^ lOlogie eiflzclncr Polymerisate. Polynterisaie cliloricrter Atliylenc. In Ullmanns Encyklopiiclie der lechnischen <e> V( 264 May-June, 1963 w o U> ON oU) u> ii ns :: i ^22Oq=i 90 seconds apd to the larger ones, about 280 seconds. Respiratory effects were mure dramatic following exposure to the smaller o-chlorobenzylidene malononitrile particles. None of the six men were able to tolerate the small particles for longer than 30 seconds. During the large particle exposures, four of six men tolerated the cloud for at least 60 seconds. The results recorded in Table II show that exposure to larger particles definitely prolonged the eye effect. While all six subjects were able to tolerate the exposure, the post-exposure effects on the eyes were quite pronounced in that recovery after ex posure to the small particles averaged about 90 seconds and the large, 280 seconds. The inability of subjects to tolerate the in halation of small (one micron) particles of o-chlorobenzylidene malononitrile or recover rapidly following inhalation of them is a function of the depth of penetration and de position in the respiratory tree. Of particles inhaled''''* those having the size of about one micron have the best chance of going beyond the upper respiratory tract and of being re tained deep in the lung. Very few, if any, latger particles (> 15 n) will penetrate be yond the upper respiratory tract. The effect of particle size of o-chloroben zylidene malononitrile aerosol of eye irrita tion may be dependent on several factors. The impaction efficiency of small particles on surfaces is of a low order,' hence deposi tion on the eye surface would be rather lim ited. However, the onset of ocular responses would be rapid due to ease of solubility of small particles in the eye fluids. larger par ticles would liuvc a much higher impucliou efficiency but the onset of irritation would be delayed somewhat due to the slowness of large particle solubility. Once begun, how ever, the irritation process would continue for a longer period than that caused by the small particles. The eyes would be cleared in both instances through increased tearing. When both the eyes and respiratory sys tems of the subjects were exposed to the ir ritant the response was predominately res piratory with the small particles and ocular for the large particles. One of six men tol erated the small particles for longer than 60 seconds; five of six did so with the larger particles. References 1. Punt*, C. L..J. T. Wiimu, T. A. Ballot, and J. L. Wilmho: Toxicological Studio oa o-Cblorobcasyli> dene MaJoaonitrUe, Tms. 9 Appt. Pkerm. 4: 656 (1962). 2. Comon, B. B., and R, W. Stouomtoni Reaction* ol Alpha Bcta.Unsaturated Dinitrilee. J. Amtr. Cktm. See. SO: m5 (1928). 9. Punt*. C. L., E., J. Owini, and P. J. Gutsntao: Controlled Human Expoauen to thCUorvixiuylidtiw Maloaoaitriic. AMA Arek. Snvir, Htmltk 6; 966 (1969). 4. Owens, E. j., and C. L. Punt*: Seme Considers* lions in Wind Tunnel Studies I Aerosob. Preseated at tho 53rd Annual Meeting ol the Anar. Inst. Cham. Eng., Washington, D. C. (Doc. 1960). 5. Mat, K. R.: The Cascade lapnetor. J, Set. IsU. . ito (1941). 6. Eisimbud, M.: Retention, Distribution, and Elimina* lion of Inhaled Particles. AMA Arek. Hi. Hyg. 6; 214 (1952). 7. Punt*. Aerosol C. L.: Studies. Some Armed PAosrpeeecttsCkoelmP. ajr.tic1le2: Sue in (1958). 8. Mitchau., R. 1.: Retention of Aerosol Particles in the Resguatory Tract. Amer. Rea. Jlei). Diseases 92; 9. Ran*. W. E., and J. B. Wosto; Impaction ol Dust and Particles on Surfaces and Body Collectors, /ad. 9 Smg. Cktm. 44: 1971 (1952). -^ X an 2 J$ i mcc Medical X-Ray Exposures The U. S. Public Health Service through its National Health Survey has published a survey report entitled "Volume of X-Ray Visits." The data gath ered for this report are based on a continuing household interview survey which shows that on the average there are 48 visits each year for medical x-rays for each 100 persons in the population. In genera), persons between the ages 45-64 years reported the highest rate of use of x-ray. One-half of all medical x-ray examinations were made in facilities other than hospitals and doctors' offices. Most examinations were for diagnostic purposes and the chest was the most frequently exposed area. Copies of the report are available from the Superintendent of Documents, Government Printing Office, Washington 25, D. C., at 40 cents per copy. Effects of Single and Repeated Exposures of Humans and Rats to Vinyl Chloride D. LESTER, Pli.l).,* L. A. GREENBERG, !>h.D., and W. ROBERT ADAMS, M.D.t . Laboratory of Applied Biodynamics, Yale University and Department of Pathology, School of Medicine, Yale University, New Haven, Connecticut 0 Rats exposed eight hours daily to vinyl chloride at concentrations of 2% for three months and 5% for 19 days exhibited changes in liver and spleen weight and in red and white cell counts. Except in the case of liver, tissue alterations did not accompany these changes. The alterations in liver morphology were within the normal range and were not pathologic in character. Because other facets of the animals' response, such as rate of growth, serum transaminase and hemoglobin, were unchanged, it is suggested that the present threshold limit value of 0.05% need not be lowered. Introduction npHE TOXICITY of vinyl chloride has been reviewed recently.1,M Because the threshold limit value of 500 ppm is based on limited data4 using vinyl chloride less pure than that now obtainable* the effects of acute exposure in man and rats and long term exposure in rats was investigated by us in 1959 and is described here. Our data do not support the conclusion of Torkelson, et al. that the threshold limit value should be reduced ten-fold; indeed their data indi cate a need for further studies prior to any revision of the threshold limit value. together with a trace of air and carbon dioxide. Tails I Analyst, of Vinyl Chloride Monomer 1 Acid Acetylene Aldehyde Sulfur Phenol Non. Vul. Water Color Amay 0.0 1:2 0.0 (0 PPM 170 ppm w.w 99+16 Methods Experimental Material The vinyl chloride monomer was supplied by the Perkins Plant of Solway Process Di vision, Allied Chemical Corporation, in four 100 lb. cylinders with the characteristics shown in Table I, presumably differing ma terially from the vinyl chloride used by Torkelson, et al.1 only in the presence of 60 ppm of the inhibitor, phenol. Gas chro matography of the liquid phase indicated the presence of more than 99% vinyl chloride, Presented at the T\*eniy-ibird Annual Meeting ol the American Industrial Hygiene Association, Washington, D. C.. May, 1962. This work was supported in part by a research groat from Allied Chemical Corporation sad in part by U. 8. Public Health Service Grant C-2738. #Preseat address: Biochemistry and Physiology, Nelson Biology Laboratory, Rutgers-The State University, New Brunswick, New Jersey. tKecipicnt ol u. S. Public Health Service Senior Research fellowship No. SF-37. Desired concentrations were obtained by metering air and vinyl chloride through flow meters calibrated for these gases and pass ing the appropriate flows through a 2-liter mixing chamber. The concentration was also continuously monitored by a thermal conductivity meter calibrated for vinyl chlo ride versus air. The desired concentration of vinyl chloride was maintained with less than 5% deviation. The total gas flow was about 50 liters per minute (1pm) in all but one of the experiments. Five experiments were conducted: (1) a five-minute exposure of human beings to concentrations of vinyl chloride ranging from 0.0 to 2.0%; (2) an exposure of rats (Sher man strain rats from Rockland Farm, New City, N. Y.) for as long as two hours with concentrations up to 15%; and (3, 4, and 5) 265 ' 266 May-]une, 1963 exposures of rats to concentrations of 8 to 10% for 15 days, 5% for 19 consecutive days and 2% for 92 days. Pathological The experimental and control animals were killed by ether inhalation after expos ures to 2, 5 and 8 to 10% vinyl chloride were completed, Each animal was autopsied according to standard practice. In addition to the gross examination of all animals, all the livers, kidneys and spleens were examined microscopically and some animals received a complete microscopic examination. Heart, lung, liver, spleen, urinary bladder, testes, prostate, ovary, brain, spinal cord, pituitary, tibia, pancreas, stomach, small and large intestine, adrenals, kidneys, uterus, fallopian tubes, thymus, thyroid, parathyroid, eye, knee joint, bone marrow, skeletal muscle, salivary glands and skin were removed from each animal and preserved in 10% buffered for malin. All tissues were examined grossly both at autopsy and after formalin fixation. Following fixation, representative samples of all tissues were processed according to stand ard histological procedure and stained with hematoxylin and eosin; separate specimens of liver were stained for fat with the Flam ing Rtd technique. The animals receiving such a complete examination of the tissues listed included two males and one female rat that had been, exposed 15 times and one female rat exposed ten times to the 8 to 10% level; eight experimental and nine control animals surviving the 5% exposure; and 20 randomly selected rats, equally di vided as to experimental and control groups and to sex, exposed to 2% vinyl chloride. The marked increases in liver weight ac companying the exposures to 2% and 5% of the gas, the decrease in spleen weight in the 2% expsoure and the reported kidney changes in exposure to 500 ppm* led us to examine these particular tissues with a blind technique, thus excluding the operation of any bias or prejudice from the judgments. All slides, including duplicates, were ran domly numbered so that it was impossible to distinguish, without the code, which had been experimental and which control. The slides of the liver, spleen, and kidney were examined and classified, then recoded and re-examined; in this manner a measure of the consistence and reliability of the pathol ogist's technique was obtained. This con sistency was nearly perfect in the case of liver slides, and only slightly less so for spleen and kidney. The results of these examina tions are reported in the appropriate follow ing sections. Results Experiment l Because the main objective was the deter mination of the effect of long term exposure to vinyl chloride, the maximum concentra tion' of the gas to which humans might conceivstbly be exposed without any imme diate acute effects was deteimincd; this con centration tlicn became the basis for deter mining the concentration used during the 92-day exposure of rats. Three men (26, 35, 50 years; 86, 78, 73 Kg.) and three women (25, 40, 55 years; 64, 52, 61 Kg.) were exposed twice each day, separated by a 6-hour interval, for three successive days to six different con centrations of vinyl chloride: 0.0, 0.4, 0.8, 1.2, 1.6 and 2.0%. The concentrations were presented in a different order to each* sub ject to make it possible to factor out any possible adaptation to either the gas or the experimental situation; the 0.0% concentra tion was included so that some assessment of suggestibility could be made. Until its conclusion, the subjects were told neither the effects to expect from the expos ure nor the purpose of the experiment; nor was information vouchsafed as to the con centrations that were used at any time. The subjects each sat in a chair separated from the gas mixing equipment by a screen, a simple plastic breathing mask affixed over the face, covering the mouth and nose. The rate of air or air-gas mixture passed through the mask was sufficient (50 1pm) to prevent any dilution effects from the atmosphere. After five minutes of breathing the mixture, the exposure was terminated and the sub jects were asked to compare their feelings at this time to the time immediately Industrial Hygiene Journal 267 prior to putting oh the mask; no suggestions of any kind were made. The responses of the subjects are summarized in Table II. It is apparent that the maximum concentra tion causing no effect in any subject lies be tween 0.8 and 1.2%. From the responses it is evident that vinyl chloride causes clearcut intoxicating symptoms which can serve as adequate warning signs of its presence. thesia for two hours; on removal to air, there was an uneventful and prompt recov ery. Experiment 3 Some notion of the distinctive and specific pathology that might be caused by vinyl chloride was our object in exposing rats to a concentration of 10%. Table II Responses of Human Subjects to Varying Concentrations of Vinyl Chloride . Per Cent Concentration Rwpoeie 0.0 N* dMTerencee reported by Subject! 1, 2, 4, 6 and S. Subject II "iKsiiil. din/'. 0.4 No didrrfucei reported by *U aubjecla. 0.0 No difference* reported by Subject! I. 2. 4, 3 aitd o. Subject J: "atiubily beady'1 12 SNubjedciltfer2e1o( cuenis_ urreep,orgtesMdssbeywbSatubujeincty! _ I. it ,m4iddalned 5.j eapbwre. Subject '6. reelings iwuusuing bead. "Jul 1.6 Uke RltioR icai". No effect repurled by Subject 5. All olben report veriest! degree! of laluaketion wilb diaaisieaa, light- tory cum; (kcae lyaprome dice(speared rapidly upon termination ol the' eepoeure. 2.0 AD subject! reported intonicaling effect*. Subject 1 reporting a headache that penwed lor 90 minutes. Them symptom* appeared carher in the exposure than at 1.6% and the symptom* were more intense then at 1.6%. Experiment 2 To gain further insight into the intoxicat ing effects of vinyl chloride rats were ex posed to varying concentrations of vinyl chloride for periods up to two hours. The effluent gas from the muting chamber, at the desired concentration, was passed through a 10-liter all-glass exposure chamber con taining two rats. At a 5% concentration in toxication is moderate but the righting rcllux is lost; imoxiiulioii is more intense at 6% but the righting reflex is still present. This reflex is lost at a concentration of 7%; the corneal reflex disappears at a concentra tion of 10%. On removal from the chamber, the animals return to the pre-exposure state rapidly. One animal was sacrificed after ex posure to the 10% concentration and showed no visible gross pathology. Exposure to a concentration of 15% resulted in deep anes thesia within five minutes. Effusion of fluid from the mouth preceded respiratory failure in one rat after 42 minutes; autopsy revealed edema and congestion of the lungs. The sec ond rat was maintained under this deep anes Thirty-six rats, equally divided as to sex, were divided randomly into an experimental \ and a control group; the 18 experimental rats were exposed to the gas in a 1100-liter steel chamber. The concentration was initial ly rained rapidly to the desired level by ad mitting vinyl chloride without admixture with air until the diluent from the chamber attained the desired level as noted on the thermal conductivity meter. A fan within the chamber, connected by a flexible cable to an electric motor outside of the chamber (thus avoiding the hazard of an explosion), mixed the vinyl chloride with the air with in the chamber. Thereafter, the effluent from the 2-liter mixing vessel was admitted to the chamber; to conserve gas, the through put of this highest concentration was 20 1pm. T)ie experimental rats were exposed daily from 0830 to 1630 hours while the control animals were exposed from 0000 to 0800 hours. At this concentration, as already noted, rats lose consciousness, regaining it five to ten minutes after removal to air. After two consecutive 8-hour exposures, how ever, the appearance of the animals sug gested that there would be no survivors if this concentration were maintained for the con templated 15-day period; consequently, be ginning with the third exposure, the con centration was reduced to 8%. The test was interrupted for one day after the sev enth daily exposure because of a mechanical breakdown. Of the group exposed in this fashion, three female rats died, after the sec ond, fifth and fourteenth exposures; the two animals that died earliest were replaced with substitutes for the remaining exposure pe riod; eight female rats were thus alive at the end of the fifteenth exposure. Female rats exposed 10 and 15 timet were autopsied BFG36304 EOOZTGt'Z 09Qj q 268 May-June, 1963 Table III Cluiificmtion of Morphologic Changes in Liven TaslbIV Classification of Morphologic Changes in Kidneys Description iNi swelling, no verueUe, vbjttfe. Slight iweQini M cU*, only a lew Mmi vcuul or one, jlnwelgt vwbW bui conprciied. S Mo4mle swelliag of ceils, mom cells with definite fine to Medium vacnoles, sinusoids compreeeed. 4 Marked swelling of cells, large irregular "vacuoles or clear spaces, r--pmtioa of suraaoids. Changes local In dairibistioe. S Similar to 4 but changes more widespread and difliieo* Description Oil* well ittfsTivnl, rw VmhuIimiIuii ><! "*yl inUin" lnw, l glMtnSMiitfeiulipsiMtlWirililitnslg. lobule*. OlkerwM u I. Ak*t 2' but with more exteaaivc vecuoUution end `ityknoMt*' IndudUg proximal collecting lubtuei in cortex. At S but with vacuolimuon end 'pykiMMu" extend- ing to convoluted tubules. pleural adhesions which were interpreted as at the termination of the exposure; the re maining lix rati were autopiied 15 dayt later, five of Uiew rati having been exposed 15 timet and the sixth rat 13 timet. The mortality wai greater among the male rata: representing regions of healed pneumonia. All other organs and tissues were within normal limits, with no differences between experimental and control animals. The experimental animals sacrificed at the only two malet turvived 15 expoturet, the termination of the exposure received a com remaining malet, and their replacement!, plete histologic examination. The lesions in turviving only an average of eight expoturet. the lungs of the three animals in this group The two male ratt exposed 15 timet were showing gross pleural pathology were seen autopiied at the termination of the expoiure. to be due to acute focal necrotizing pneu There waa no weight gain in the initial monia in varying stages of organization. dayt of the expoiure to thit concentration, al Some pulmonary edema was present as well though after the ninth day tome retumption as diffuse infiltrates of mononuclear cells of growth teemed to occur, pouibly an in in the alveolar septae. Some areas of meta dication of the development of tolerance to plasia were present in and near the regions the effects of the gas as the exposure con of pneumonia and were interpreted as secon tinued. Upon termination of the exposure, dary to the pneumonia. growth returned promptly at the same rate The parasitic liver cysts seen grossly were as the control animals. Both at the 16th and at the 30th days, there appeared to be no differences in liver: body weight ratios confirmed microscopically. The liver sections stained for fat revealed individual variation of some degree but no significant deviation between experimental and control rats, al from normal. The coded slides of the livers though too few livers were weighed at the were classed according to the descriptions termination of the experiment to make mean ingful comparisons of thit ratio. The external appearance, coat and tail, of all the animals was within normal limits. in Table III while kidney and spleen were judged according to the criteria in Tables IV and V; Figures 1, 2, 3, 4, and 5 are About a third of the animals had parasitic liver cysts. No differences in appearance, color, consistency or degree of congestion were observed between the livers of experi mental and control animals. The lungs of three experimental animals sacrificed im mediately upon cessation of the exposure had numerous focal fibrinous pleural exu dates overlaying nodular yellow-brown pa renchymal lesions which had the appearance of regions of acute necrotizing focal pneu monia. Of the six experimental animals sacrificed two weeks after the exposure, the lungs of two revealed a few adherent fibrous illustrative of the class descriptions in Table III. There were no significant differences in the scoring of the groups, although there was a class "5" and no class "3" in the rats killed at the termination of the exposure, whereas there were no livers in class "5" among the control animals. There were no class "5" livers among the experimental rats killed two weeks after the exposure; the slides were evenly divided between scores of 3 and 4. Kidney slides from the experimental ani-' mals were not graded differently than from the controls but all spleen slides from ex perimental animals received the highest score, differing significantly from the con trol spleens, although some controls also received such high scores. Experiment 4 These preliminary tests seemed to indicate that vinyl chloride was an anesthetic gas which might also act as a lung irritant. In order to assess this feature of its action, to highlight significant pathological features and to avoid the potentiality of damage arising from anesthesia alone, five female and five male rats, matched with controls, were ex posed for eight hours daily to five per cent vinyl chloride in air for 19 consecutive days. The experimental animals were placed with in the chamber at 0830 and removed at 1630 and the control animals from 0000 to 0800 hours To prevent contamination of food or water, both groups of animats were placed within the chamber in empty cages; hence experimental and control animals were de prived of food and water for eight hours daily. The requisite concentration of the vinyl chloride was attained initially as in Ex periment 3, but the chamber was ventilated at 50 1pm. ' Although the body weight of the experi mental rati decreased initially, this trend was reversed by the fourth exposure, the rate of growth thereafter being no different than the controls. The drop in weight at the start and the subsequent resumption of growth was paralleled by an apparent increasing tol erance to the gas as the exposures continued. At the start, the intoxication of the rats was marked, instability of the hind legs being a prominent feature of the exposure. With each exposure, however, there was an obvious diminution of these symptoms, so that by the fifth or sixth exposure, it was not possible to distinguish any evident symptoms of neu rological deficit. Hemoglobin determinations during the ex- 270 May-June, 1963 Table VI Formed Element* of the Blood *t Termination of Exposure to 6 and 2% Vinyl Chloride Coatral--S% <t) RBC XlP/mn* Mw 8.D. i.u 0.40 t.rr 0.76 WBC XlOVmm* Mas S.D. IS.ST S.7S 7.M 1.0S Lymptocytw Mho 00.4 8.D. 0.7 2.0 s.s N*utr fphila 9 Uiu 8.D. 0.4 o.s 4.0 0.1 "p" Lm Um Caatral--f% (M) Siptl.--*% "p~ las ihM 0. 01 OSS .m 0.M NS 0. 01 11.04 s.os f.lt s.os 0.01 NS 04.0 4.00 0.7 0.04 0.01 N8 IS.41 4.71 0.01 4.04 0. 01 poture period revealed no difference between experimental slnd control groups. On the twentieth day experimental and control animals were anesthetized with di ethyl ether, blood was drawn by cardiac puncture and 1/9 volume of 0.1 A/ sodium oxalate was added to the blood. The ani mals were then killed with an overdose of the anesthetic and autopsied. Measurements of hemoglobin, prothrombin time, hemato crit, red cells, white cells, differential white cells and serum transaminase were performed on the blood drawn. Serum transaminase, hematocrit values and prothrombin times were normal for both groups. Table VI lists the values for tome of the formed ele ments of the blood. Monocytes and eosino phils formed only a small proportion of the white cells; no differences between control and experimental animals occurred. The red cells were somewhat elevated and the white cells lower in the experimental group. Table VII shows that the liver:body weight ratio of the experimental animals was significantly elevated. All five male experimental animals ex posed to 5% vinyl chloride had coats which were somewhat thinner than normal; the tails of these animals were scaly. The three fe male experimental animals and all the con trol animals had normal coats and tails. One male experimental animal had fibrous pleural adhesions on the left tide; the fibrous nature of these adhesions suggested that the Table VII Uvor and Bpluun Weights uf flat* Kxpoavd Li Vinyl Chloride Industrial Hygiene Journal 271 process was several weeks old and probably not related to the exposure. Both experi mental and control animals had parasitic liver cysts. No differences in appearance, color, consistency or degree of congestion were noted between the livers of the two groups. The other organs and tissues were within normal limits in their gross appear ance, with no differences between experi mental and control groups. With the exception of the pleural adhe sions in one animal, the microscopic appear ance of all the organs and tissues was nor mal. The gross observation of parasitic liver cystes in all animals was confirmed micro scopically. Liver sections from all animals were stained for fat, but none revealed evi dence of increased fat nor were there any differences in intracellular fat between the two groups. Classification of the liver slides for the morphological designations of Table III showed differences between the control and experimental groups. The mean score of the control group was 2.93 and that of the experimental group was 4.56, with only one control animal being graded "4" and no experimental animal being graded less than "4". The differences between the means was thus highly significant, yielding a "p" of lest than 0.001. No differences in kidney or spleen slides between experimental and control animals were noted. Experiment 5 Because human exposure to vinyl chloride seems unlikely at concentrations of the gas iimcli greater than the concentration causing signs of intoxication, that it, at 1.2 to 1.6%, the long term exposure of rats was conducted at a concentration of 2.0%. Sixty rats, each weighing about 75 grams, were separated randomly into two groups of 15 males and 15 females and placed in eight separate cages. In the week before the ex posure was started, the rats were observed, weighed twice and blood withdrawn for hemoglobin determination. The experimen tal animals were exposed in the 1100-liter chamber to 2.0% vinyl chloride for eight hours per day (0830 to 1630) on Monday through Friday for a period of three months. The control animals were exposed to 0.0% of the test gas, that is, to a flow of 50 1pm of air, in the same chamber as the experi mental group for eight hours per day on the same days of the week. No food or water was present in the cages during either ex posure. All rats were weighed at approxi mately weekly intervals; hemoglobin deter minations, from tail blood, were made at monthly intervals. In neither body weight nor in hemoglobin values were there any sig nificant differences between the control and experimental groups. During the course of the exposure, there were five deaths; of these, four occurred in the control group. No data from these ani mals are included in any of the tables. On the 89th day blood was withdrawn from the control animals under anesthesia as previously described (Experiment 4); these animals were then killed with ether and autopsied. A similar procedure was followed on the 92nd day for the experimental ani mals. The livers and spleens of sdl animals were weighed prior to fixation in formalin. The mean values of the tissue: body weight ratios are shown in Table VII. The dif ferences in the means, were in all instances significant, the livers larger and the spleens smaller in the experimental as compared with the control animals. No significant differ ences between the groups appeared In the values for hematocrit and prothrombin. The serum transaminase was not determined. Monocytes and eosinophils showed no dif ferences between the groups; values for the other blood elements are sliown in Table VI. The external appearance of all animals was normal. Parasitic liver cysts were pres ent in all animals. There were no differ ences in apiwarunce, color, consistency or degree of congestion between the livers of the two groups. Alt other organs and tis sues were similarly normal, no differences between the groups being apparent All the organs and tissues examined histo logically were within normal limits, no path- 272 May-June, 1963 ology being evident in either experimental or control animals. The parasitic liver cysts seen grossly were confirmed microscopically. Liver sections stained for fat revealed normal variation, but no animals had increased intracellular fat nor were there differences between the experi mental and control animals. Graded in accord with the morphology in Table III, to produce some lingular or characteristic pathology. It cannot be said that this goal was achieved, the results being questionable and uncertain. Lung lesions were certainly present but these could not be ascribed with certainty to any irritant properties of the gas since they might well have arisen from the long-continued anesthesia; there was an ap parent regression of these lesions in rats al the liver slides revealed differences between lowed a 14-day recovery period. The pres the groups. The mean score of the control ence of pneumonia certainly raises the pos group was 1.58, that of the experimental sibility of an acute toxic effect on lung tis group 3.63. No liver in the control group sue at these concentrations; however, the scored snore thus 2 and none in the ex pneumonia could just as well be caused by perimental group scored leu titan 3; one liv secondary infection during the severe cen er scored 5. Because there was no overlap tral nervous system and respiratory depres the differences between the means are high sion, an interpretation favored somewhat by ly significant. the diffuse lesions and by the irregular oc There were no differences in score for the currence of the pneumonia. spleens in the two groups, but the kidney The kidney and liver changes described slides of the experimental animals scored by Mastromatteo, et a!.* in rats exposed for significantly leu than their controls. 30 minutes to 20, 30 and 40% of vinyl chloride, were not observed here, although 15 repeated 8-hour exposures to an anesthe Discuuion tic concentration is also a relatively severe The data from the present investigation stimulus. The findings in the lungs agree confirm the acute effects to be expected from with the relative lack of effect found by various concentrations of vinyl chloride: concentrations below 1%, when exposure is limited to five minutes, cause no ob Mastromatteo et of. in rats exposed for 30 minutes to 10% vinyl chloride, except that continued exposure, for days, does result in servable intoxicating effects; five minutes, mortality. The relative lack of pathology as however, is shorter than the time necessary to reach an equilibrium level in the circula tion; from behavioral observations in the the result of 30 minute exposure at 10% found by Mastromatteo et at. would seem to support the view that lung lesions found tat, it may be estimated that in five minutes some two-thirds of the equilibrium level is reached; consequently a concentration of 0.6 after repeated exposures could well arise from the anesthesia and not from some ac tion peculiar to vinyl chloride. There was to 0.7%, if long continued would not pro no indication at either the 2% or 5% level duce intoxication. At the concentration rises of any untoward or other effects upon the above this level the intensity of the intoxicat lung tissue. ing signs increases until at a concentration of 7% the righting reflex it lost; at 10% the corneal reflex disappears and at concentra As an overall measure of general health, body weight and rate of growth are sensitive indicants. Even in the exposure to a con tions of 15% and above respiratory failure centration of 5%, which at first produces a takes place. Vinyl chloride thus acts as an marked and severe intoxication, the sharp anethetic gas, its depressant action increasing drop in the weight of male experimental with increasing concentration of the gas in animals teen at the start of the exposure was the air breathed, the corresponding increas soon reversed so that by the end of the 19- ing neurological deficits ending in death at day exposure there was no difference be concentrations greater than 15%. The pur tween experimental and control rats of wV * pose in exposing rats to concentrations caus either sex. Body weight and rate of growth ing anesthesia (8 to 10%) was an attempt similarly showed no differences between the Industrial Hygiene Journal a c 273 groups in the 2% exposure. It must be em view of the wide range that the :liver: body phasized again that the growth of the rats weight ratio may encompass (Table VII). during the 5% exposure support the observa Rather this increase may signify a non-spe tion of the rat's behavior which indicated cific response to metabolic derangements oc that there was a rapid development of toler ance to the intoxicating effects of this con centration. casioned by mild and moderate intoxication for daily 8-hour periods. From the data ob tained here, it is not certain that histopatho- Neither the 2% nor the 5% concentrations logical change would have occurred had e*caused changes in the prothrombin time, posures been carried out for longer limes, t hematocrit or hemoglobin values. At both In the paper by. Tori^elsonbjs&r the 2% and the 5% concentrations, ' the white cell count was lowered significantly, altlidugh still well within the normal range. The increase in red cells, although signifi cantly elevated itt the 5% exposure, was hot Correlated with'changes in the hemoglobin content. The increase in concentration of the vinyl chloride is associated with a greater fall in the white cells and a greater (and significant) increase in the red cells at the 5% level. Although lymphocytes and neu trophils are increased, only the change at the 2% concentration unlike the previous cell changes, reaches the statistically signifi cant level. It is difficult to know if these changes have any toxic significance, since no tissue changes were seen upon microscopic examination that would account or be as sociated with a drop in the white cells or an increase in red cells. The decrease in spleen: body weight ratio is in a direction opposite to that usually associated with a severe drop in white cells; although the white cell count did not suffer a severe drop, the decrease was substantial at the termination of the ex posure. pathqlqgical chpngcs in the., liver and iq* crraisid livcriUxly ' weight ratios are ('t^lrted in male rats exposed to 500 'ppm vinyl chloride for 4.5 months. That there pa causal relation between the, reported btffc topathpkgy'and the increases in liver^body weight ratio ii evident frptp the .extensive data gathered by these investigators. Female rats ex|x>ted to 500 ppm vinyl'chloride for 4.5 months showed no statistically significant increase in liver weight but are reported to have histopathological changes iff the liver. Female rats exposed to lower concentrations (100 and 200 ppm) for six months had sig nificantly increased liver:body weight ratios but no pathology. On the other. band, rab bits of both sexes exhibited livet*. pathology without showing any increase in liver weight after exposure for six months to a concen tration of 200 ppm. The authors correctly [mint out that organ: body weight ratios may well be artefactual, illustrating the point by the significant decrease in kidney weight found in female rats exposed to 50 ppm for six months; such rats exhibited no changes when exposed to higher concentration!. By The only finding suggesting a specific toxic action of vinyl chloride is the increase in liver weight on exposure to 5% for 19 days and to 2% over 92 days. The increase in liver weight is not only highly significant statistically but is also substantial, amounting to a 30% increase over the controls. It is unfortunate that no information is available as to whether this increase is reversed on dis continuing the exposure. The increase in liver weight may be interpreted as indicating the same token, but overlooked by the authors, the increased liver:body weight ratio in female rata at 100 and 200 ppm is with equal reason artefact because no sta tistically significant increase occurred at 500 ppm. Apparently, also, species differences are of importance in the reactivity to vinyl chloride, male guinea pigs suffering a signi ficant decrease in their liver-.body weight ratio when exposed to 100 ppm for six months. alterations in water, electrolytes and protein content of the liver parenchyma, but that such changes presage the development of actual histologic lesions is not certain in There are six possible combinations of the presence or absence of pathology and in creases, decreases and no change in liver weight. The one combination not observed z 9 0 jg QOOZTGtZ 274 *A < . i i May-June, 1963 by Torkelson,1 at al. U liistopatliological change associated with a decreaie in liver weight Obviously, if five of the six possible combinations have been observed in a rela tively small sample, no causal connection can be said to exist between these two measures. Changes in the liver:body weight ratio may well have some toxic significance, but if they are unaccompanied by histopathological alterations, increased fat content or serum transaminase changes it is impossible to' conclude that taken alone they signify flW-shqjy 40 times those used by Torkelson, el al. If any reliance is to be placed in a dose-effect relationship, pathology of some considerable degree should have been found in'pur ex periments. Yet only morphological, altera tions of the character already described and pictured were seen, which, in our knowledge and experience, are of no pathological signi ficance. Whether the explanation resides in a difference between the rat strains used by us and by Torkelson ft al. or elsewhere is not known, but without additional data it is impossible to resolve the contradiction. . ....... ............_ . . basis of the present data, and the V `' that ihe liver:body weight ritfds'iC.tlieTraU'* seeming. unimportance of the liver weigh* reuse>d. as contro.han.iitiaAh. in th- e-J*5.%. siIIf*pqsI#ur'eta- _tg_ ::~\v__e_re sig_nifi<*n_tlw--hig.b..e..r....t.b..a. .n..,.\.'.t.h. .e-ptpefii-'J.out --- -- andU. . T'ava-I. aLaM aS-.a!' aVf/i furthei^_identt.'k1 (fhan_ge of' the lwAilflihn-.' pres-' * out- > *'. anfihfTJ m ;tW24C, l-eU&posctmfi^ Thbis1`' eftrirf'tthfirreashholldd"1 limit value of"S"5O0O0 pppm feems :: y-'n` Illustrates weil the fact that though control unwarranted. /'animals aroused, unknown and non-specific changes in.jjtg environment, time of the year, Summary temperature,'''diet, etc., may be responsible for changes in Organtbody weight ratio with out at the same time producing pathological alterations in'the organ. From 5-minute exposures of human sub jects to concentrations of vinyl chloride rang ing from 0.0 to 2.0%, it is estimated that a prolonged exposure to a level of more than Similar considerations apply to the de crease in spleen weight; .here, not only was pathology not observed, but there was no difference in the morphological character at either the 2% or 5% level between the experimental and control groups. 0.6% is necessary to produce minimum, symptoms of intoxication. Rats exposed for up to two hours to higher concentrations ex hibited moderate intoxication at 5%, lost their righting reflex at 7% and the comeal reflex at 10%. Respiratory failure occurred at 15%. If the exposure to 10% was long Unlike the interstitial and tubular changes in kidneys of rats exposed to 500 ppm of vinyl chloride reported by Torkelson, et al., was the lack of any pathology in our animals exposed to 2% and 5% and the fact that the only morphological alteration in which a continued (two 8-hour daily exposures), mortality increased; death was apparently caused by a pneumonic process, but it .was impossible to decide whether this was the result of a primary action or secondary to the anethesia. significant difference between control and Rats exposed eight hours daily to 5% for , experimental animals occurred (kidney at 19 days or to 2% over 92 days did not show 2%) indicated that the control animals were any lung involvement. These levels had no further from "normal". Because it is un effects upon growth rate, hemoglobin, hema reasonable to attach toxic significance to tocrit or prothrombin time. At both con changes associated with a control air ex centrations there were increases in the liver: posure, it is our belief that the morphologi- body weight ratio and decreases in the white cal alterations we have observed should not cells; at 2% the spleen:body weight ratio be interpreted as manifestations of pathol decreased and at 5% there was an increase ogy. in red cells. Industrial Hygiene Journal 275 die changes in die (ornicd elements of the blood. The increases in liver:body weight ratios were associated with morphological alterations in the liver which appeared to have no pathological significance, while no meaningful morphological alteratioris were evident in either kidneys or spleens. Because, in the long term exposures, it was impossible to attach any toxic significance to the changes noted or to observe any histopathology, and because other aspects of the animals' reactions, such as growth rate, were unimpaired, the presently accepted threshold limit value of 500 ppm for vinyl chloride, one-fortieth of the concentration tested here, seems to offer an adequate margin of safety for human exposure. Acknowledgment It is a pleasure to acknowledge the tech nical assistance of Malcolm Nicholson, Frederick A. Putt and Miss Lillemor Wall- mark. References 1. von Omtimocn, W. F.i Tko Hologonattd t*j; Toxicity and Potential Dontort. U. S. Mile Hulth Service, Publication 414. Govonuttat Priatfa( Office, Wuhiagtoa, D. C. (1955). 2. Muiwmattio, E.; A. M. Fiama, H. Gmm. ud H. Danucu: Acute lubalatioa Twkitf of vajl CMoride to Laboratory Aalawb. ^urr. M. Uyg. Assoc. J. )h 994 (Oct. I960). 3. Toksum>n, T. R,, P. Ovum, aarf V. K. Rowe: Tbe Tonicity of Vinyl Chloride ae Deteraiiaed by Ea>ef6 Eiimurt of Laboratory Anlmab. Amm. /ad. ffjy. AttaTJ. 22: 354 (Ocl. 1961). 4. Smvth, *H'. "P., J'a.: *Improved Comamalcalloa Hy |iM eteedercb fur Daily labalolloo. Amor. lad. Jfy|. AAtna*. } Hi 129 (1956). 5. Hhatty, f. a., W. F. Yant, and O. F.' Waitsi Acute Knpooae of Quiets Pic* to Vapor* of teat* Now Oaa . motctal Ornate Comoouada V. VUayl CUerida. Fib fir Hoallk Jltparu (VJ.) 4S: IMS (Juag. 19)0). Sources and Use of Toxicological Information The New York University Medical Center in cooperation with the American Industrial Hygiene Association will present a course on Sources and Use of Toxicological Information. The course will be given October 14-18, 1963, at the Onchiota Conference Center, Sterling Forest, Tuxedo, New York. The course is designed to acquaint those concerned with advanced methods of securing and interpreting pertinent toxicological information. Application and principles will be stressed rather than details of experimental toxicology. The design of the course eliminates the need for specialized scientific back;round so that all administrative and technical persons having responsibilities ?or use of toxicological information can benefit. Guest lecturers who are spe cialists in selected fields will supplement the staff of N.Y.U. Institute of Indus trial Medicine for presentation of the subject material. Areas to be covered are: biological principles involved, sources of toxicological information, appli cations to implant problems, .Federal regulations, and requirements of various agencies. ' Inquiries and registrations should be directed to New York University Medical Center, Institute of Industrial Medicine, 550 First Avenue, New York 16, New York. The registration fee is $150 with i deposit of $25 required'. Ac commodations (double occupancy) at the Onchiota Conference Center for the evening (dinner) October 13 through lunch October 18 are available at $21 per day including meals (payable to the Center on departure). . <* BPG36308 The concentrations to which the rats were No gross or microscopic changes were I) subjected in these experiments were at least found in any tissue that was correlated with 4002161-2 130 . Annals New York Academy of Sciences 48. Dugois, P., P. Amolaad, B. Db Bignicourt A J, Leorand. 1972. Acropathie polyvinyliquc professionnelle. Bull. Soc. Franc. Dermatol. Syphiligr. 79i 197. 49. Eckardt. R. E. A R. Hindin. 1973. The health hazards of plastics, J. Occupa tional Med. 15; 808. 50. Edmondson, H. A., R. L. Peters, H. H. Frankel & S. Borowskj. 1967. The early stage of liver injury in the alcoholics. Medicine 46; 119. 51. EubopaCiiemie. 1972. Handelsblait GmbH. DUsseldorf, West Germany. T T 19S7 TnHmiri.i Invigalnfty-JniL^dit Th. Wi)linn-Ar-WilMng~ -GompanyrBultimorerhldr' 53. Filatova, V. S. A E, Sir. GaONSaERO. 1937. Sanitarno-gigienileskie usloviya truda v proizvodstve polikhlorvinilovdl smolyi 1 meryl ikh ozdorovleniya. Gigiena Sanit. No. 1: 38. 54. Filatova, V. S.. L. I. Balakhonova A E. Sit. Gronsbero. 1958. GlgicniJeskaya kharakicrisiiki proizvodstva khloristovo vinila. Gigiena Truda Prof, Zabolevuniya 2(1): 6. 55. Filatova, V. S., E. Sh. GRONsaeaa, N. A. Smirnova, E. A. Stvlova A I, V. OresckeviC. 1965. Voprosyl gigienyi truda I sostoyanie idorov'ya raboiikh, zanyaiyikh na proizvodstve laleksnovo polivinilkhlorida. Gigiena Truda Prof. Zabolevaniya 9: 9. 56. Filatova, V. S. A V, A. Antonyuzjienko. 1971. Gigieniicskiye usloviya truda i professioual'caya zabolevaemosi' raboiikh proizvodstva suspenzionnovo polivinilkhlorida v dinamike za ryad let. Gigiena Truda Prof. Zabolevaniya 15(4); 12. 57. Fisciier, J., II. Munoschenk A R. Wolf. 1965. Milzszinligraphlc mil l-Dromomercuri ('"Ilg|-2-hydroxypropan (BMHP). Fortschr. Gebiele Roemgenstrahlen Nuklcarmcd. 103: 349. 58. Fisciier, 1., R. Wolf A 11. Gamm. 1973. Die Milzszlmigraphie. Dtsch. Arztebl. No. 7; 401. IQ.ri.iN-B ,1 IQAfl Tumnri nf |jyrr In nf ih> tin, t: "grtrinr-PN 3isf-edili h D. LipplUCUn Company. Philadelphia, Pa; 60. UitsiOS, C. 1. 19/1. Acroosieolysis in PVC workers. Med. Bull. Stand. Oil Co. JUiy. 49. 61. GOntiier, O. 1956. Die Kunstttolfe und ihre arbeilsmedizinlsche Dedeutung. Zemr. Arbeiumed. 6i 156. 62. Harris, D. K. 1953. Health problems In the manufacture and use of plastics. Bril. J. Ind. Med. lOt 255. 6). Harris, D. K. A W. G. F. Adams. 1967. Aero-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. J. 3i 712. 64. IUnschler, D., Ed. 1972/1973. Gesiindheitsschldliche ArbeitsuolTe. Toxikolo- gisch-arbciismcdizinische Bcgrtlndungen von MAK-Werten (Maximale Arbeiu- phttz-Koiuemrationen). Verlag Chemie. Weinheim, West Germany. 65. IIerri.e, K. 1963. Polyvinylchlorid. In Ullmannt Encyklopadie der technfschen Chemie. W. Foerst, Ed. 3rd edit. Vol. 14. Urban A Schwarztnberg. Milnchen, West Germany. 66. Hervieux A Tessier. I9S9. Quclqucs observations d'exposition et d'intoHrance aux dlrivtj vinyliques et tux risines Ithoxyliqucs. Aren. Maladies Profess. 20i 61. 67. Ioer, F. L. 1970. Portal hypertension in the presence of normal liver morphology. Ann. N Y. Acad. Sci. 176(1): 115. 68. International Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. I: 387. 69. International Labour Office. 1972. Encyclopaedia of Occupational Health and Safely. Geneva, Switzerland. Vol. II: 1467. fRTSii, J. Ov-H163 Usinfrnatfd hydracarbont: I. Allphwie. Jn Industriat-Kyaiane Tuilmnn/y Vi.4-JTi TnyirrAi^^. p. sir CacjaN ft p rr, satL-.iarPubiijIiLi s. No wYni k" HTYi Kih fnlrr 71. Iavitt, N. B. 1970. Clinical and experimental aspects of sulphobrontophihaicln and related compounds. In Progress in Liver Disease. H. Popper A F. Schaffner. Eds. Vol. ill. Grune A Stratton. New York, N.Y. 72. Judaii, J. D.. A. E. hi. McLean A E. K. McLean. 1970. Biochemical mechanisms of liver injury. Am. 1. Med. 49; 609. 73. JdiiE, S. A C. E. Lance. 1972. Sklerodermleartige Haufvcriinderungcn, Raynaud- Syndrom ur.d Akrccsteolysen bel Arbeitcrn der PVC-hcrsUlicndcn Industrie. Deut. Med. V/cchsci.r. 97s 1922. TOOCTGl'Z 609Od9 Marsieller el ol.\ Splciiomcgalic Liver Disease i31 74. Kelly, R. E. 1973. Vinyl chloride and acroosieolysis. J. Occupational Med. 15; 75. Kl8aStBs.kin, G. 1969. Toxic and drug induced hepatitis. In Diseases of the Liver. L, Schiff, Ed. 3rd edit. 1. B. Lippincott Company. Philadelphia, Pa. 76. KLiNce, O. A H. W. Altwann. 1971. Morphologie toxischer Hepatosen. Miinch. Med. Wochschr. 113; 1529. 77. Kluge, T., H. Sommerschild A A. Flatwark. 1970. Sinusoidal portal hyperten sion. Surgery 68: 294. 78. Kramer, C. G. A i. E. Mutciiler. 1972. The correlation of clinical and environ mental measurements for workers exposed to vinyl chloride. Am. Ind. Hyg. Assoc. J. 33; 19. 79. Lanoe, C.-E., S. J Oise, G. Stein A G. Veltman. 1974. Die sogenannte Vinyt- chlorid-Kranklieit--eine berufsbedingte Syslcmskicrosc? Intern. Arch. Arbcits- mcd. 321 i. 80. Leake, C. D. 1934. The role of pharmacology in the development of ideal anes thesia. I. Ain. Med. Assoc. 102: 1. B 06 /* Wsst Gumartyr 82. LfFivRg, M. I. 1972. Internationales Symposion der Werksiirzte der Chemischcn Industrie, 27-29 April 1972, Ludwigshafen. As cited in Stein tl a/., 1973. 83. Lehmann, K. Q. A F. Flury, Eds. 1918. Toxikologie und Hygiene der techni- schen Losiingsmiitel. Julius Springer. Berlin, Germany. 83. Lindner, H.Q73jLaparoscopy in alcohol-induced liver dlscase^Gastrocnleroiogy 5Tone A A. I. Sandison. liver. J. Praamthuoil. 1im09/i 3^9/.. Mali Eli, K. U. dL Rr L:" ftraL'iiuu: 196 1, InduclriaLToniaolagy and Dei umlulup pftan tr ift--lh PiuduUiuir and PrULEVSlllE'of~ Plaj;ies.-Etsevitr Publisiiiui Gumuairr.-/-- ' J.88. Maltoni, C., M. Cresfi A P. R. Burch, Eds. 1973. II International Symposium on Cancer Detection and Prevention, Bologna, April 9-12, 1973. Excerpta Mcdlca Int. Congr. Ser. No. 275. 89. Marin, A., J. Strauss, R. Miciiiels, I. P. Benoit, R. Baltie A C. Pierre. 1967. Acro-osteolyse d'origine professionnelle (Travail prfsenie i la Ligue Francaise conlre le Rhumatisme, stance du 18 janvicr 1967). Rev. Rhumat. 34s 340. 90. Markowitz. S. S., C. J. McDonald, W. Fethiere A M. S. Kerzner, 1972. Oc cupational acroosieolysis. Arch. Dermal-' 91. Marstellea, H. J., W. K. Lelbacii, R. Boiiner A G. Veltman. 1973. Cluonis in der PVC-Produklion. Deut. Med. Wc *1 92. KlASTROMAmo, E., A. M. Fisher, II. Cti halation toxicity of vinyl chloride to ial I. 5t 394; Dull. Hyg. 36i 244. 91.. MtYFRS. M B--1060 nrrupAttOP^1 lll1 -Baltimorei hid. " 94. McCord, C. P. 1970. A new occupation! 12: 234. 95. Mikkelsen, W. P., H. A. Edmondson, .' H 0} Reynolds. 1965. Extra- and inirahcpai (hepaloporul sclerosis). Ann. Surg. 162 H 96. Misoeid, V.( H. J. Srot.ri.unN A S. S Vinylchlorid-Poiymcrisaie und/odcr de 0 JW C. E. Unoe, H. G. chaden bci Arbeitcrn iger. 1960. Acute inAm. Ind. Hyg. Assoc. A-Wilkins CuilipJliy. f!>oo /CL. I. Occupational Med. G. Redeker A T. B. sion wiihout cirrhosis ir Intoxikalion durch :. Haul Geschlechtskr. 481 425. 97. Morris, I. S.. T. Htut A A. E. Read. 19: Ann. Rheumalic Diseases 31i 316. 98. Nettlesiiif, A. A W. ]. Fink. 1961. Neo Ihorotrasl. Am. J. Clin. Pathol. 35; 422 Nj a 00 d portal hypertension, following injection of inzelner PolymeriiateC 99. Oettel, II. 1963. Gewerbeloiikologie u,. I'olyinerisate chloricrlcr Alliylcne. U\ Ullmanns Encyklopadie der lechnischen 1 A-156/842 ABSTRACTS OF PAPERS Vol. 64, No. 4 svav I risraomc 8TCM06COH. C. J. Llahtdele. G. Poaner. P. Sherlock end 8. J. Wlneuer. Outroenterology Sonic*, Deportment of Medicine, Haaorlal Sloon-Kettering Conner POSITIVE ESOPHAGEAL CVTOLOGV WITHOUT DETECTABLE NEOPLASM. H.N. HMmon and A.E, Cocco. Cuter, Bow Tork, n.T. The situation which ellowed Beaumont to look Into tbs stouch of St. Martin vas Department of Medicine, Division of Gastroenterology, The Johns Hopkins University unique at tbs tins but has becoae coanooplaea with tbs ermtlon of operative gastro School of Medicine, Baltimore, Maryland. intestinal stoaas. Standard gastrointestinal fiberscopes are usually too large In The early diagnosis of esophageal cancer Is the only hope of alleviating an disaster to pus sully through operative stcau- Since the fiberoptic bronchoscope otherwise poor prognosis. We have seen four patients In whoa positive cytology hu a such --it'1'1t- dlssMter (ACMX 0.56 ca) than tbs standard duodenoscope (ACM 1.25 speclnens were obtained during evaluation for dysphagia. Carefully performed ca), e decided to use the former u a stoaoacope. Tbs first 5 patients examined In roentgenography, endoscopy and multiple biopsies failed to demonstrate a lesion. this Banner ers presented, all bed feeding gastrostomies. Their staunchs could not The patients were followed with diagnostic procedures for 6 to 30 months before a be erulned by tbs usual endoscopic means because of esophageal obstruction. In the lesion was defined. One patient was explored and had hiatus hernia repair with first patient a permanent esopbsgsal narrowing vas ruled cut when the cerdloeeophageel no other lesion visualized. All patients eventually had exploration from an nOd Junction vas entered from the stomach and the esophagus sxealned. The functional nature of the patient's disorder vas suspected but could not be confirmed by standard abdominal approach with endoscopy from above with discovery of primary esophageal carclnoaia In each case. The question of appropriate management of patients who endoscopic or x-ray techniques. In the second patient the response to radiotherapy demonstrate positive cytology of the esophagus and negative concomitant diagnostic O and chcawtherapy of an adenocarcinoma of the cardie was documented and gastric biopsy, brushinge and washings for cytology were obtained. The third patient had a pharyngo- studies Is raised. U> laryugeetaeqr'for earalnou and vas evaluated for tbs possibility of a gastric tuner, On gtaaosoopy and cytology studies were negative. The fourth patient hod a stricture of U> the distal esophagus and wu being evaluated for further dilation or surgery. The fifth patient was one year postresectlcn for oarolncaa of the cardla who developed a smooth stricture la the aoastoaetlc area. The brosiohoscope was passed to the area under fluoroscopic control and no evidence of recurrent tumor was found. Brush cyto logy was negative. The advantage of using the fiberoptic bronchoscope le that It le available on many thoracic services and could be shared by gastroenterologists. Its flexibility makes it safer than the more rigid Instruments that are generally used for this purpose. Areas can be visualised that are blind or cannot be reached by the acre rigid iastruaents. LAPAROSCOPY IN ALCOHOL-INDUCED LIVER DISEASE II. LlnUiimr Medical Department, German Red Crone Huapltal, Hamburg, Gormany. Percuteneoue liver biopsy with the Menghlni needle will confirm the dlagnoelm of fatty liver, but oannot be relied on to reveal The ...................... -- wnuuDLiir i in . A. M. McCloy end E. R. Nobles. infcfMn.tn.i ( Oepertment of Medicine and Surgery, Baptist Memorial Hospital, ) Memphis, Tennessee. Atent of when it (tun n*t uiJirniippil Th investigation is bated on 668 U|Wi'(iacu)iiaa and a'Oliu blo|>tioa ( A patient with Hill was found to have recurrent upper gastrointestinal perfonatd in th latt two yar. Laparoscopy was performed on 22 bleeding doe to OGP, a cod)(nation of findings not previously reported. patlants out of 281 with fstty livar, and on 49 patisnts out of 146 with fatty liysr and sisssnohymal activity. Thars was alcohol abuse in 78 Jf of 83 patients with finely nodular cirrhosis (laparoscopy perfonsed in 52 patients) and in 53 ^ of 83 put louts with pontueorotio cirrhosis (laparoscopy in 46 pntients). It is much easier to classify 1 Serlel endoscopic exanlnetlons end gestrophotogrephy permitted not only an iccurate diagnosis as to the source of the bleeding (DGP), but also docu mented recurrence after Initial gastric resection end then e marked pro- \I mtheismsiuocnosaInotfhethesizloewaenrdesnoupnhtiaegrusofanpdoleypnltdiremagsasesst,ricwhriecmh nualntitm. aSteiglmy oIindvoosclvoepdy, tbs disease by inspecting the liver through the laparoscope than by eorutinlslng f snail biopsy spuclnen* In 38 % of cases the presence of finely nodular cirrhosis was not appreciated on biopsy* Blind percutaneous biopsy with the Menghlni needle gave even worse results. Out of 83 cases of postnecrotic cirrhosis the proportion incorrectly classified was auch the saae (30 *). The laparoscopic appearance of acute alcoholic hepatitis* fatty liver (alone and with psrlportal fibrosis), fatty cirrhosis (alone and with 1 c>e-rliaycs oanfdthmeesceonlotenricanadrtsemriaolgl rbaopwheyl reenvdealilveed rnoscavnaswceurlearnoarbmnaolr.maSliteyl.ectAivefast- i log gastric aspirate was negative for malignant cells, and bad a Ml of 6.7 with !14 neq/Hter of acid (volume 14 ml.). Serum gastrin was normal (142 PG per ml.), f imaunoglobullns IGA and IGG were low (83 and 260 mgs. t, respectively). Because \ef the high Incidence of malignancy associated with DGP, total gastrectomy was performed; pathologic sections showed diffuse benign polyposis without neoplasm. Tbe patient recovered end has had no evidence of recurrent lesions or anemia. cholsstaaia), toxic-degenerative cirrhosis and postnecrotic cirrhosis (as an advaneed fora of alcohol-induced liver daaags) are Illustrated by characteristic sxaaplss. Zisve's ayndroae is characterised by the Ihe frequent association of atrophic gastritis end hypochlorhydrle with both prsasnes of cholestasis, while the aost striking feature of aleohol- WT end DGP Is an Interesting observation, but an uncertain factor In the induced siderosls is the chocolate-brown colour of the liver. Pathogenesis of the lesions found In our patient. Endoscopy Is the most valuable The stain advantage of laparoscopy combined with needle biopsy of the , fiagnostlc procedure In patients with gastric polyposis end should be performed i liver under direct vision is that it enables the physician to estab lish the diagnosis with certainty. (periodically after sub-totel gastric resection; If recurrences develop total ijlotrectoanr is a procedure of choice, t 800CT6f-2 `130 . Annals New York Academy of Sciences 48. Ducois, P., P. Aaiblard, D. Da Diqnicourt St J. Leorand. 1972. Acropathle polyvinytique professionnelle. Dull. Soc. Franc. Dermatol. Svphiligr. 79s 197. 49. Eckarut, R. E. A R. Hindin. 1973. The health hazards of plastics. I. Occupa- u'onal Med. I is 808. JO. Edmondson, H. A., R. L Perns. H. H. Frahxel St S. Bohowskj. 1967. The early stage of fiver injury In the alcoholics. Medicine 46i 119. 51. EuxoPACNEAiie. J972. Handcliblatl GmbH. DUsseldorf, Wc^ Germany^ ^ ^ -CompanysnBeltimefe, Md. 53. Filatova, V. S. A E. Sn. Gronssero. 1957. Sanitama-gigieniieskle usloviya truda v proizvodstve polikhlorvinilovoi smolyi i meryl ikh ozdorovleniya. Gigiena Sauls. No. 1: 38. 54. Filatova, V. S., L. I. Balakhonova A E. Sit. Gronsderq. 1958. Gigieniteskaya kharakierisiika proizvodstva khloristovo vinila. Gigiena Truda Prof. Zabolevaniya 2(1): 6. 55. Filatova. V. S., E. Sn. Gronsbero, N. A. Saiirnova, E. A. Stulova A I.' V. Okesckevic. 1965. Voprosyi glgienyi truda 1 sosloyanic ztlorov'ya raboiikh, zanyatyikh na proizvodslve lateksnovo polivinilkhlorida. Gigiena Truda Prof. Zabolevaniya 9i 9. 56. Filatova, V. S. & V. A. Amtonyuzjiinxo. 1971. Giglcnitcskiye usloviya truda I professional'naya zabolevaemost* rsboiikh proizvodstva suspenzionnovo poli vinilkhlorida v dinamike za ryad lei. Gigiena Truda Prof. Zabolevaniya 15(4): 32. 57. Fischer, J. H. Mundschenk Sl R. Wolf. 1965. Milzszimigraphie mil 1-Bromomercuti (,nHg)-2-hydroxypropan (BMHP). Foruchr. Geblete Roentgensfrahlen Nuklearmed. 103t 349. ft PO'J 58. FisetiaR, J., R. Wolf Sl H. Gamai. 1973. Ola Mllzszihiigraphfa. Otscli. Arztebl. _ No. 7: 401. 13--G.'Lfa, S...S IPAQ Tnmri nl |Ivit In ntoecpA nf lh> Ua.-1 - -- 3rd editi-lrU. LippIlllUll Company. Philadelphia, Pa. ~ 60. Gitsios, C. T. 1971. Acro-osleolysis in PVC workers. Med. Bull. Stand. Oil Co. 31(1): 49. 'i. Guniiuii, O. ivio. Die KunjlsioiTc und Hire arbellsmedlzinlsclie Dedeulung. Zentr. Arbcitsmcd. 6i 156. 62. Harris, O. K. 1953. Health problems in the manufacture and use of plastics. Bril. J. Ind. Med. lOt 255. 63. Harris, D. K. Sl \V. Q. F. Adaais. 1967. Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. J. 3t 712. 6-t. I Irnschlkr, D., Ed. 1972/1973. GesundhcituchEdliche ArbeiustoiTe. Toxlkolo- gisch-irbeitsmedizinische Begrilndungen von MAK-Werten (Maximal# Arbcits- plauKomeniraiionaa). Vertsg Chemie. Weinheim, West Germany, a 65- IIrrri.c, K. 1963. Polyylnykhlorid. In Ullmanna Hncyklopidla dir taehnlachen Chemie. W. Poem, Bd. 3rd eijlt. Val. West Germany. - |4 Urban A 5Sc`hwaninbcrg. Mlincheni 66. ItEKvieux Sl 7'esstea. 1959. Qucloues observations d'exposillon et d'intoldrance aux dlrivls vinyllques el aux rdstoej fthosyiiqucl. Arch. Maladies Profess. 20i 61. 67. Uer, F. L. 1970. Portal hypertension in the presence of normal liver morphology. Ann. N.Y. Acad,Sci. 115. 68. International Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. I: 387. 69. International I.Aeoua Office. 1972. Encyclopaedia of Occupational Health and Safely. Geneva, Switzerland. Vol. II: 1467. /W"10 W, Faasall Ji D. D.-Isisb, Edi^jiHcj;- 71. JaviTT, N. B. 1970. Clinical and experimental aspects of sutphobromophthaleln and related compounds. In Progress in Liver Disease. H. Popper & F. SchafTner, Eds. Vol. Hi. C-.-ur.c St Stratton. New York, N.Y. 73. Judah, J. D.. A. c. M. McLean A E. K. McLean. 1970. Biochemical mechanisms of liver injury, A.r.. j. Med. 49i 609. 73. liltiE, S. A C. E. L/.nce. 1972. Sklerodermleartige Hautvcrhnderungcn, Raynaud- Synti.-c.r :r.`S / fcroosteolysen bel Arbclfcrn der PVC-herilclIcnden Industrie, Deui. i-Jer-;. V'cchschr. 97t 1922. TO0frT6FZ ZI9Oda 0 Marsicllcr el al.: Splcnomegalic Liver Disease 131 74. Kelly, R. E. 1973. Vinyl chloride and acroosceolysis. J. Occupational Med. 15: Kl8a5t8s.kin, G. 1969. Toxic and drug induced hepatitis. In Diseases of the Liver. L. 75. SchiiT, Ed. 3rd edit. I. 0. Lippincott Company. Philadelphia, Pa. Klinoe, O. Sl H. W. Altaian*. 1971. Morphologie toxischer Hepatosen. Mlinch. 76. Med. Wochschr. 113t 1529. 77. Kluoe, T., H. SoAttiExscitiLD Sl A. Flataiarx, 1970. Sinusoidal portal hyperten 78. Kxsaioaine.rS, uCr.geGry. S6t8s!.2E94. .Mutciiler. 1972. The correlation of clinical and environ-, menial measurements for workers exposed to vinyl chloride. Am. Ind. Hyg. 79. LaAnsgseo,c.CJ..-E3.3,: S1.9.JOiie, G. Stein St G. Veltaian. 1974. Die sogenannie Vinylchlorid-Krankhcii--cine bcrufsbcdingic Sysicmsklerose? Intern. Arch. Arbcits- med. 321 I. 80. Leake, C, D. 1934. The role of pharmacology in the development of ideal anes thesia. J. Am. Med. Assoc. 102: I.__________________________________________ a+r I rnutlfijki ...... I A, --If i.intT- Mr.iiminjiR M.iin' Oennariyr 82. Lf6vre, M. J. 1972. Inicrnaiionaics Symposion der WerksSrzie der Chemischcn Industrie, 27-29 April 1972, Ludwjgthafcn. As ciled in Slein ti al,, 1973. 83 LenMANN, K. B. St F. Flury, Eds. 1938. Toxikologie und Hygiene der lechni- schen Lbsungsmitiel. Julius Springer. Berlin, Germany. 84. Lester, D., L. A. Greenberg Sl W. R. Adaais. 1963. Effects of single and re peated exposures of humans and rats lo vinyl chloride. Am. Ind. Hyg. Assoc. 5. 8 oofc~ 24s 265. .86 MacSween, R. N. M,, J. M^Vetters, S. K. Ross, J. Ferouson, J. M. JohnSTONe Sl A. T. Sandison. (I?!)) Haemangio-endotheliai sarcoma of (he liver. Q. PjihgLiMlii._________ rimiuuimrinU^PiOCTOmK "O^TIBtiCj7^LiJcvier^iHH>Tiiiiin^^CTnTpSi.. _ 88. Maltoni, C., M. Crespi Sl P. J. R. Ourcii, Eds. 1973. II International Symposium On Cancer Detection and Prevention, Bologna, April 9-12, 1973. Eacerpta Medica Ini. Congr. Ser. No. 275. 89. MAaiN, A., 1. Strauss, R. Miciiiels. 1. P. Benoit, R. Baltie & C. Pierre. 1967. Acro ostiolyse d'originc professionnelle (Travail n'*ni6 h la Llgue Francaise contre le Rhumatismc, sfance dJu 18* i'ar-'r 90. Markowitz. S. S., C. J. McDonald, W rfl cupailonai acrooslcolysis. Arch. Derm ^ ^ Rhumal. 34i 340. S. Kerzner. 1972. Oc- ft 91. Marstellsr, H. J., W. K. Lelsacii, R. ^ Roiiner Sl O. Vietnam. 1973. Chronl to C. E. Lange, H. O. schiden bei Arbeilern in der PVC-Produktlon. Deui. Med. Wi 92. Mastroaiatteo, E., A. M. Fisher, II. Cl halation toxicity of vinyl chloride to lal iqer. I960. Acme inkm. Ind. Hyg. Assoc. J. St 394; Bull. liyg. 36: 244. VJ' '93_MAYfaS.-M. B__1060 rtmipalinnal U.:alL -Jl.lllimutSi hid. 94. McCord, C. P. 1970. A new occupational W 12; 234. 95. Mikkelsen, W. P., H. A. Edaionoson, R. Reynolds. 1965. Extra- and inirahtpatic (hepaloportal sclerosis). Ann. Surg. 162: 60 V ON 96. Misgeld. V.. H. J. Stolpaiann A S. Sctiu vl Vinylchlorid-Polyinerisale und/Oder dcren , os : Wilkinj Cumpuny. Occupational Med. Reoeker A T. B. i without cirrhosis Hoxikationdurch ut Gcschlechlskr. 48i425. 97. Morris, ). S., T. Htut Sl A. E. Read. 1972. Sc . Ann. Rheumatic Diseases 31: 316. 98. Nettlesiiif, A. A W. J. Fink. 1961. Neoplasms....... ihorolrasi. Am. J. Clin. Palhol. 35; 422. tal hypertension. liver following injection of 99. Ouitel, If. 1963, Gewerbetoxikologic und Physiologic einzdner Polymcrisate. Polymcrisale cliloriciier Alhylenc. In Ullmanni Encyklopddie der (cchniichcn fbt>o /C. HAEMANGJO-ENDOTHELIAL SARCOMA OF THE LIVER R. N. M. MxcSweek, J. M. Vetters, Sheila K. Ross, J. Ferguson, J. M. Johnstone and A. T. Sandison University Departments ofPathology and Medicine, Western Infirmary, Glasgow, Department ofPathology, Grimsby General Hospital, Lincolnshire, and Department of Fibre Science, Strathclyde University, Glasgow Plates X-XIV Haemanoio-endothelial sarcoma of the liver, also known as haemangiosarcoma and Kupflfcr-cetl sarcoma, is an extremely rare tumour. Videbaak (1946) reported two peaks in the age distribution of this tumour, one at 8 mth and the other at 49 yr. Blumenfield, Fleming and Johnson (1969) reviewed the literature on juvenile haemangio-endothelioma of the liver and found 37 cases, only five of which were solitary tumours. Ninard (1930, cited by Edmondson, 1938) accepted 44 published cases in adults. In the present communication we report the three adult cases of haemangioendothelial sarcoma of the liver that have been seen in this department since 1900. In particular we wish to draw attention to the difficulties that were presented by two needle biopsies in one of these patients, and to an attempt that was made to exclude a possible occupational factor in one case. Materials and methods The three cases occurred in two males aged 55 and SI yr, and in an 81-yr-old female. Tissues collected at necropsy were fixed in 4 per cent, formaldehyde in saline and embedded in paraffin wax. Sections were stained as a routine with baematoxylin and eosin (HE), and by Masson's trichrome method. Selected sections were stained for reticuUn (Gordon and Sweets' method) and by the periodic acid-Schiff (PAS) method. Case reports Casei A male fibre-glass worker aged 53 presented in Feb. 1970 with a 3-mth history of general ised pruritis and increasing mental apathy. He admitted to moderate alcoholic exoess, but gave no previous history of jaundice. Clinical examination revealed mild icterus marked facial telangiectasis with a few spider naevi, and early bilateral Dupuytren's contracture. The liver was enlarged and was palpable three finger-breadths below the right costal margin. Liver scan showed a diffuse uptake abnormality compatible with cirrhosis. Liver biopsy was performed. He was treated subsequently with prednisolone, phenergan, amitriptyline and cholestyramine with some transient subjective improvement. However, there was con tinued objective evidence of progressive hepatic dysfunction, and, when he was readmitted in hepatic precoma in Aug. 1970, a liver scan showed a more severe diffuse reduction in isotope uptake. A further liver biopsy was obtained. There was slow deterioration and death in hepatic failure occurred in Dec. 15)70. Received 16 Feb. 1972; accepted 20 Apr. 1972. i. Vats.--voi. I0 (H7J) MV., i TH!ci MATf.RIAl. MAY BE PROTECTED BY COPYRIGHT LAW (TITLE 17 U.S. CODE! 40 MacSWEEN, VETTERS. ROSS, FERGUSON, JOHNSTONE AND SAND1SON Necropsy. The body was jaundiced, and there were numerous spider naevi. The peri toneal cavity contained 500 ml of free fluid. The liver weighed 2 leg, and showed evident macronodular cirrhosis. On section several cystic areas were present, and in addition there was diffuse, mottled, pale yellow and haemorrhagic tumour. No metastases were found. There was bilateral pulmonary oedema and congestion. Case 2 A male shipyard worker aged 51 was first admitted in June 1963 with a 3-4-wk history of listleasness, progressive abdominal swelling, ankle oedema and occasional diarrhoea. A rfinlnni diagnosis was made of hepatic cirrhosis with portal hypertension, oesophageal varices and hepatocellular failure. Diuretic therapy effected some improvement in his ascites and oedema, but his general condition deteriorated and he died in Aug. 1963. Necropsy, the body was jaundiced, and there was gross bilateral ankle oedema, and 1 litre of tree fluid in the abdomen. The liver weighed 2-6 kg. The right lobe was largely replaced by an irregular tumour 10 cm in diameter, haemorrhagic and partly necrotic. The left lobe showed a macronodular cirrhosis. Oesophageal varices were present and the spleen was enlarged to 310 g. The lungs showed bilateral lower-lobe oedema. No metastatic tumour was found. Case 3 (Grimsby General Hospital) A housewife aged 80 was first referred to hospital in May 1967 because of recent rapid and severe Increase in abdominal girth, accompanied by increasingly severe central abdominal pain of approximately 12 months* duration. She was grossly oboe, with some peri-umbilical bruising^ and an ill-defined abdominal mass was palpable. She was not considered suitable for laparotomy, and died 2 wk after admission. Necropsy. There was an excess of fluid in the peritoneal cavity. The liver weighed 2-8 kg. and was largely replaced by haemorrhagic, partly necrotic tumour, with some related areas of fibrosis. The lungs showed mild chronic bronchitic changes and bilateral basal bronchopneumonia. Microscopic findings Case 1 The two biopsies submitted showed similar features, but posed considerable diagnostic difficulty. Macronodular cirrhosis was present and, in addition, a continuing active hepatitic process, characterised by a moderately intends lymphocytic and plasma-cell infiltration of the portal areas and fibrous septal with erosion of the limiting plates (fig. 1). The most striking feature, however, was a fairly generalised hyperplasia of what appeared to be Kupffer cells. These cells were larger than normal Kupffer cells, and in some areas lined dilated sinusoidal spaces. In other areas small groups ofindividual hepatocytes were surrounded by the proliferating cells resembling littoral cells (fig. 2). Mitoses were not noted. Although a differential diagnosis of haemangioendothelioma was considered at this time, the possibility of the changes being reactive, possibly to fibre-glass or some other exogenous agent, was also entertained, particularly since no solid tumorous aggregates were teen. Post mortem histological examination of the liver clearly established a diagnosis of haemangio-endothelioma. Areas similar in appearance to those shown in figs. 1 and 2 were readily found (fig. 3), but, in addition, there were areas of clearly neoplastic tissue composed of elongated spindle-shaped cells. Mitotic activity was low. Large blood-containing spaces lined by tumour cells were MacSween, Vetters, Ross, Ferguson, Johnstone ano Sanoison Haemanojo-endotheual sarcoma of the liver Plate X iff aoain evlrlanl and a BFG36315 COObTGbZ 24914004 `001X aH `lUiApmrad 3|imfoi| fiuuou pgs*|dai mij tarads n|ittcA psuii -Ipo-Jnouini stj| tno -jjuinfj jni| uiaiioui -)od !| 3i3 -- > oy IX mivy mil mi VHioiivs ivnaiiKHiNn-oioNVHsvn NOSK1NVS (INV dNaiSNHOf `NOSnOM^ 'SSO>| `sMl I I 1\ `NIlM'v'JVW , `Oily *3H UMoqs II** A|JIBJ *| 'jSASMOq 'UJSIIVd dAUBUUOj odlut tqj, 'jnouim jo tail ptduios aioui aqi jo MaiA i3MOd-q8;H t WD-'OI 'oy 001 X `3H `uotusoduios |p>9|putds jo put istduios *j jnoumi' aq) qotqM in vajy i *ny--'f, wj *0CJX 3H `ptTfJtUJ ||Sm jt lusitsuiojqs JtdXqJttpnu put 'u/iiqdJCHUoafd jnoumt aqi jo oautjtaddt |p>t|putd aqx *j acts U| utq) sajXoostdaq aqi oi poitpj Xpjm|)Uj nt( tit t||tt asaqx ,J9A!| J uouojifijui jpa jiHHuni jo mia jftMod>q9;f| *2 ast^--g *oif oq! x `3H -tajAsojtdaq put spjoa opedaq jo uoptjitdas qiiM joaij aqi jo uopej)|pu`i |ja>jnouin) asnpiQ ZXK>~'L f*j I1X 3XV3J tiAII 3 HI JO VWODtVS nvn3H10CJN3*01DNVW3VH NOS1QNVS ONY SNOiSNHOf `NOSflOWJ 'SSOtf *St3U.3A 'N33MS3VW 2491400S BFG36317 *0R X 3H fifa>iv<bt| pu fipo jnouim UMMiaq uofitpi amufiu; 9qi pu (ijsj) cairifojfffv |(*wnotuni Moqt ot m jaMod-q&fH X ^13--$! 'Ofj 001X -HH ltt|<to<mio-JR!Bdn^| Mnjpp put taovds jijtwwa tnojaumu `sj) padmft-afputdt tatduioa jo ajy c 0O--Tl *oy 24914006 BFG36318 nix MAH 3HI AO YHmXYt 1Vn3HJX>ON3-OIDNVK3VH NOSIONVS ONV aNOXSNHOf `NOSflDMJ `SSOtf `SM3U.3A `N33MS3vW Kpi*'!mpa +?wQ 0X *3H PpyjoaJiuU|X|j|n9**A uiof tfttfodouitttf /Citfinpoui -wi*o jo tnooj 9| CHJ ***** ArL'*<? jv*,4 KUt. `05Z x *3 h siso-ioau jo wi pan?pj n pun `waned jffjnosRA |9U;|Sip OU l||1M SdteflajftJle U jpujds-jnoujni pait9uo|a 3USB|dBUV *C 9S3-- *51 tMJ *0KX *3H !oimu jo tta.it aAituatva aiv aiai|i put *uaos sis tajnSy dfiojfft *tUlXl(9QUtd J9A1| Suiatfdaj Xfftioi tajeflaiWe ||*wnouini jtiniiMJadXH *C D--*M *oij AIX uvy taAn am. jo vhoduvs ivnaHitxiNS-otONvmvH NOSIONVS ONV INOLSNUOf *NOSftOt3J '*S0>| `N33MSJVJM 24914007 BpG363l9 apurtnnpt oj pasn sbm uisaq jssbj jaM0d-M0( b anbraqaa) aq)jo uoi)btjba b nj pasn ajaM )q8q pa)aayai ptra pappusnan q)og aog x jo aopBagraSsui s )B )q8q pasuBjod pus [buuou japun pauniraxa ajaM Xaqx 'dpsjaAoa ptra apps adoasojarai b uaaMpq jsjbm ui pajanotu ptra sinojojsitn b qjtM jno ajaM J3AI| jo samaras pa)oaps XpuopuBg suoiimnumxt o\doosoio\pi M9Ai| aq) ui saprusd ssB|8-aiqg jo aauasajd aq) qsqqspa oj iduians ob ui pasn ajaM sanbjuqaa) jo sauas y (j af) saTOLurvj ssvio-aiimd jo aoNasauj aiu wm i asvo nod hbad do NouvNmvxg '(91 '8y) spaa dnonmt Xq pang saoads jBjnasBA unpiM )uasajd ajaM asaq) `j asBO ui sb `pire jnouin) siqj unpiM psaidsapiM aiaM sisarodotuasq XjBpnpauraqxa jo iooj -punoj Xpssa sbm (si -8g) jnoiunj jo sbbjb PBduioo pus (ji -8y) asnjyip aq) uaaMjaq uoijisubjx '(SI puB )>[ 's8g) ssare snojBtnoajBS opsB[dBU8 jB[npaoiadXq asaq) o) uoi)B|aj ui juasajd sbm sisojaau aAtsuajxg -oasis Xppsaj aiaM sjaunaqa jBjnasBA ou 'Suranqs upnopaj poB gfi no qjoq 'qaiqM m sassstu mourn) pqos pauuoj Xjiaijdb aijojrui jo aajSap apjapoin b paMoqs )Bqj spao padBqs-aipuids pa]B8uo|a `sbsjb asaqt uj -(ji pus n -$8g) jnouini aqjjo sbsjb pnduioo ajoui at uaas ]Bq) DBqi ssa| Xypuapisuoa sbm stqj jnq `ssajB asaqi ut uisiqdjouioaid ppm sbm aiaqx '([ pus j[ -s8g) asBa siq) ui luapiAa uib8b sbm spaa jaAi| jo sdnojS poB ]BnpiAipui puB spaa jnomnj aq) uaaM)aq diqsuoi)B|ai aiBuiput aqx tDJ punoj ajaM sjsaiodouiaBq XiBpnpauiBJixa jo iaoj ou poB `spuusqo jBjnasBA aSiBj Maj ajaM ajaqj i asBa ut sSuipug aip q)iM )SBJ)uoa u[ spuuBqa 8umiB)uoa-poo|q paup pus qjoM -auiBJj upnapai aq) u;q)iM Xbj spaa mount) aq) :(i[ -8g) ain)BU aAgstoiojoiSuB 8)t pa)BJ)suotuap Xpniap `jnotnn) aq) jo sbbjb PBduioo atom aq) ut uaAa `sunqs upnopag `mo( uib8b sbm X)iai)38 spoqpj '(oi puB 5 -sSp) ppnu apsuiojqa -jadXq X|u;bui puu pa)n8uop Xuoui qiiM 'padBqs-aipuids Xpaupsjp aiaM spaa aqX '(6 PTM g s8tj) spaa jnouin) jo pasodmoa Xpjpua )soui|B sbbjb aq) ui pus jnouin) jo SB3JB SupBjqpu; aq) u; q>oq 'uisiqdiouioa|d JBjnpaa paqjBUi ojoui sbm aiaqx '(8 `*0) snopajd aq) u; uaq) a)BUiput ssa| sbm sa)Xao)Bdaq aq) pus spaa jnoum) aq) uaaMjaq uoi)B|aj aq) )nq '(4 -8y) jaAi| iq) ui juapiAa os|B sbm spjoa a)Xao)Bdaq jo uopdrusip q)iM uopaqipui ap$B[doau asnjjiQ Z st>0 `(9 pus s *s8y) jnouin) aq) jo spuusqa jBjnasBA aq) uiq)|M paiBaddB sXbm|b pus psajdsapiM ajaM sisaiodouiaaq XjBpnpaoiBi)xa jo iaoj -sainSy ai)0)iui iBuoisnaao pus uisiqdiouioatd jB(npaa a)Biapoui q)iM `(9 a8g) aaus -JBaddB paa-aipuids }38duioa ajoui b jo sbm jnouin) aq) ssajB auios u[ (s '8y) aauBJBaddB aAt)Buuojoi8uB paugap-paM s paMoqs )Bq) sa)B8aj88B paa-jnouin) japBuis ajaM ajaq) uopippB uj ()> *8g) jaAp aq) )noq8nojq) X[asnjg;p )uasajd IB X3A17 3HX JO VNOOVVS 7Vn3H10aN3-0IDNVVi3VH 24914008 BFG36320 42 MscSWEEN, VETTERS, MOSS, FERGUSON, JOHNSTONE AND SANDISON the sample with incident light. Trial experiments had shown that in these circumstances fibre-glass gave a characteristic pattern, and a glass fragment was highly reflecting. On the basis that glass is highly unreactive, further samples of the liver were digested in concentrated hydrochloric acid and the residue was examined. Other samples were gently pyrolysed to ash and after the ash had been digested in hydrochloric acid, both the ash and the residue were examined. None of these experiments showed the presence of artefacts that could be attributed to fibre-glass or glass fragments. Ash content The abnormal liver and samples of normal liver were dried to constant weight in vacuo, and their ash content was determined after pyrolysis. The abnormal liver had a dry-weight ash content of 3-15 per cent. The correspond ing figure for the normal liver was 3-78 per cent. These experiments provided ncgnlive results, but they do not lotully exclude the presence of fibre-glass particles, although this seems highly unlikely. Discussion In the years 1900-1969 inclusive, 120 cases of primary malignant tumours of the liver have been studied post mortem at the Western Infirmary, Glasgow (MacSween, unpublished observations). Of these, cases 1 and 2 in the present report are the only instances of haemangio-endothelial sarcoma, an incidence of 1-6 per cent. Hepatic cirrhosis, cryptogenic, and of macronodular pattern, was present in cases 1 and 2. As SOI cases of cirrhosis were examined in the 70 years of review, this represents an incidence of 0-4 per cent. It is thus evident that haemangio-endothelial sarcoma of the liver is an extremely rare tumour in this area, and a very infrequent complication of hepatic cirrhosis.. The pathogenesis of haemangio-endothelial sarcoma of the liver is not clear. In approximately 40 per cent, of those reported in the literature the liver was also the site ofcirrhosis, but why such a tumour (or even hepatocellular carcinoma or cholangiocarcinoma) should arise in the cirrhotic liver is not understood. Cases of haemangio-endothelial sarcoma of the liver have been reported after thorium dioxide administration (MacMahon, Murphy and Bates, 1947; Horta, 1933, 1936; Liidin, 1933; Fruhling, Gros and Batzenschlager, 1955; Tesluk and Nordin, 1955; Wuketich and Mark, 1957; Edmondson, 1958; Looney, 1959, cited by Suckow, Henegar and Baserga, 1961; Rosenbaum, 1959), gnd in Lttdin's case thorotrast was demonstrated within the tumour cells. Hepatocellular carcinoma and cholangiocarcinoma, also, may develop after thorotrast administration, as well as other tumours in various extrahepatic sites (Suckow et al.; Grampa, 1971). Chronic arsenic intoxication also has been implicated in the development of haemangio-endothelial sarcoma of the liver (Roth, 1957, cited by Regelson et ol,, 1968; Regelson et al.). In Roth's series of 82 cases of German vintners exposed to chronic arsenic intoxication from insecticide sprays and dusts, there were 28 cases of hepatic cirrhosis, eight of HAEMANGIO-ENDOTHEUAL SARCOMA OF THE UVER 43 which were complicated by haemangio-sarcomas--a considerably higher incid ence in cirrhosis than has been reported in any other review. Ross (1932) described a malignant angioformative tumour of the liver and attributed its development to prolonged gamma-ray exposure from a lost radium needle. No particular aetiologies) factor could be cited in any of the present three cases. In particular the presence of fibre-glass particles could not be demonstrated in the liver in case 1. The features seen in the two needle biopsies obtained in case 1 presented considerable diagnostic difficulty in interpretation, and in the absence of frankly malignant tumour aggregates, the appearances were described as those of a diffuse Kupffer-cell hyperplasia. Baker, Paget and Davson (1956) drew atten tion to the presence of hyperplastic Kupffer cells in areas remote from the primary haemangio-endothelioma, and advanced this as evidence in favour of the Kupffer-cell derivation of the tumour type. These field changes were seen in all of the present cases, and it was relatively easy to see a gradual transition from an apparent in-situ Kupfler-cell hyperplasia to frankly malignant tumour cell aggregates. Hastings-James (1949) considered that the appearances remote from the tumour were caused by intrahepatlc infiltrative spread of malignant cells. It seems unlikely, however, that the degree of invasion could be as extensive as we have seen in the present material, as Baker et al. also point out. Furthermore, careful examination, particularly in cases 1 and 3 (figs. 2 and 13), showed apparently malignant cells lining hepatic sinusoids and there were no areas in which a double layer of " intact " Kupffer cells and tumour cells could be defined. Examination of our three tumours leads us to agree with the suggestion that haemangio-cndotheliomas may be derived from Kupffer cells, and the angioformative properties of the malignant cells in our cases are therefore not surprising. Foci of haemopoiesis, present in two of our cases, are quite a common finding (Edmondson). During foetal life, and in conditions of infiltrative marrow replacement, Kupffer-cell differentiation into haemopoietic stem cells is well recognised. The occurrence of extramedullary haemopoiesis in these tumours could thus be interpreted as a further point in favour of their Kupffercell histogenesis. A fairly rapid downhill course was followed in all three patients, and such a clinical pattern of behaviour is well documented (Buntine, Lyall and Renowden, 1971). Metastatic tumour spread did not occur, but in previous reports approximately 50 per cent, have shown metastases, involving lung, portal lymph-nodes, and other abdominal viscera, including occasionally the spleen (Edmondson). , Summary Three cases of haemangio-endothelial sarcoma of the liver are described. The histological features in these cases are outlined in detail and in particular attention is drawn to the appearances seen in one of these cases on liver BFG3632l eoOt'TSf'Z BFG36322 44 MacsWEEN, VETTERS, ROSS, FERGUSON, JOHNSTONE AND SANDISON biopsy, appearances that are considered as suggestive evidence of the KupfTercell origin of these tumours. The previous literature on this type of tumour is briefly reviewed. We are grateful to Dr O. Walltinson for permission to publish case 1. REFERENCES Baker, H. ds C., Paget, O. E., and Davson, J. 19J6. Haemangioendothelioma (Kupffer cell sarcoma) of the liver. J. Path. Bad., 72, 173. Buubobld, T. A., Flemmo, L D,, and Johnson, W. W. 1969. Juvenile hemangioendo thelioma of the liver. Carreer, Phiiad., 24, (33. Boutins, D. W., Lyall, 1.0., and Renowcen, V. G. 1971. Hacmangloendothclial sarcoma of the liver. Med. J. Austral., I, 201. Edmondson, H. A. 1938. Tumors of the liver and intrahepalic bile ducts. Allas of Tumor Pathology, Washington, D.C., Fascicle 23, p. 139. Fhuhuno, L., Gaos, C. M., and Batzenschlaqsr, A. I9SS. Sarcome endothelial angio- plastique generalise chcz un malade ayant subi 12 ans auparavant une injection intraarterielle et para-anerielic de thorotrast. Bull. Ais.fr. Etude Cancer, 42,339. Cramta, G. 1971. Radiation injury with particular reference to thorotrast. In Pathology Annual, ed. by S. C. Sommers, London, p. 147.' Hastinos-James, R. 1949. Malignant haeinangioeiuloihelioma (haemangioblastoma) of the liver. J. Path. Bad., 61,49. HoaTA, J. DA S. 1933. Lebcisarltom einer Frau; 3 Jahrc und 2 Monate nach Thorotrastinjektion. Chirurg, 24, 218. Horta, J. da S. 1936. Late lesions in man caused by colloidal thorium dioxide (thorotrast); a new case of sarcoma of liver twenty-two yean after the injection. Arclu Path., 62, 403. LCdin, M., Jr 1933. Haemangio-endotheliomatose von Leber und Milz be! Thorotrastspeicberung. Schweir. Z. altg. Path., It, 987. MacMamon, H. E., Murphy, A. S., and Bates, M. I. 1947. Endothelial-cell sarcoma of Uver following thorotrast injections. Amer. J. Path., 23, 383, RSOSUON, W,, Kim, U., OsriNA, J., anii Holland, j, F. 1968. Hcmangioendothelial sarcoma of Uver from chronic arsenic inlusicalion by l-'owler's solution. Cancer, Phiiad., 21, 314. RjQSENSAUM, F. 3. 1939. Lcbcrsarkom nach Thorotrast. Dt. med. Wschr., 84,428. Ross, J. M. 1932. A case illustrating the effect of prolonged action of radium. /. Path. Bad., 35, 899. Suckow, E. E., Hsneoak, G. C., and Baxeroa, R. 1961. Tumora of the Uver following administration of thorotrast. Amer. J. Path., 38, 663, Tesluk, H., and Nordin, W. A. 1933. Hemangioendothelioma of Uver foUowing thorium dioxide administration. Archi Path., 60,493, VtDgaAAK, A. 1946. Haetnangioendocbelionia of the liver. Acta paedktt., Stockh., 33, 129. WuwnCH, S.. and Mask, T. 1937. Doppelcardnom nach Thorotrait-Arteriograpbie. Z. Krebsforsch., 62,93. OTOl'TBl'J! THE DISTRIBUTION OF RADIOACTIVE LEAD (<>Pb) IN THE CEREBELLUM OF DEVELOPING RATS John A. Thomas*, Frederick D. Dallenbach and Manorama Thomas Institutfiir Neuropathologle and Instilut Jlir Experimentelle Pathologie, University of Heidelberg, Heidelberg, Wtit Germany Plates XV-XVJJ Although toxic effects of lead have been known from early times, it was not until the eighteenth century that its effects on the nervous system were studied. Since then many investigations have been made on human material. Pentschew and Garro (1966). who introduced the first experimental model of lead encephalopathy by using newborn rat* and poisoning them through their mothers' milk, produced severe oedema and haemorrhage of the brain, mainly in the cerebellum. From their experiments, Pentschew and Garro postulated that lead encephalopathy, like Wernicke's encephalopathy, was due to a chronic metabolic dytoxidosis of the capillaries. Ule, Kolkmann and Brambring (1967) concluded that the oedemaof Wernicke's encephalo pathy owed ht origin to a hydropic swelling of the neuropil, that developed Independent of vascular involvement. This view was further substantiated by the work of Wegener, Kolk mann and Rein (1968) by meant of an autoradiographic study using radioactive-labelled serum albumin. Thomas, Dallenbach and Thomas (1971) in furtherstudies on experimental lead encephalo pathy tn suckling rata demonstrated degenerative changes In the endothelial cells of numerous cerebellar capillaries. This finding was associated with massive oedema, platelet thrombi and Purkinje-cell changes. Whether the damage to the capillary endothelial cells represented a direct toxic action of lead, or an indirect injury due to a vitamin deficiency or a deficiency ofother substances, could not be determined. In an effort to localise lead in the developing rat cerebellum, we have injected radioactive lead intrapcritoneally and studied the cerebellar tissues by means of light-microscope and electron-microscope autoradiography. Matosuals assd methods Four Wistar female rats, each with a t-day-old Utter, were used for this experiment. Two litters served as controls and two litters as the experimental group*. One experimental group was given an inlraperitoneal injection of 10 pCi and the other one of S pQ of radio active lead (*>*Pb). Individual-rati from each group were killed at 1, 3,6,24,72 and 168 hr her the injection. Before the animals were killed, a heparin anticoagulant (Liquemin) with a short-acting barbiturate aa anaesthetic was given intraperitoncaUy. The vascular system was perfused with 3-3 per owt. glutanldehyde through the left cardiac ventricle, at Received2SOct 1971; accepted! Mar. 1972. Present address; St John's Medical College. Bangalore-34. India.