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R&s 113963 BIO-MEDICAL.' RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 _______ 76 Duplicate.in all cards:--> yr i 1 ^ year as-1961-- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space T-A-r:sc.. f j >.i' | ________________________ ________________________________ : 77 78 Sub-Index Code 51 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 ' _____________________________________________________ 61 62 21 T <C^- / 22 SI ' y - Zt t?. t-c-- ,//yy- 23 24 w Source (Journal, Vol., Number, Pages,Date) 1 62 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 3IEH DEFECTS xsis axd DJUnMQHDvmz 15 THE PROVINCE OP CT105 FOR ACC OF THE SDSETHiE D EFFECTED P HAVTNICAN- -.000. XjecSDFTLLE 2485 >. Kite * 26.57 1 9.25 i 2.41 t 6.8* 7 30.98 37.82 I I R&S 113964 DETECTION OF LIVER Ad) SPLEEN PATHOLOGY AFTER VTKTL CHLORIDE EXPOSURE--POTENTIAL OF GKET-SCALE ULTRASOUND AND DOPPIEZ TECHNIQUES Kenneth J.W. Taylor. M.D., Pb.D. Pa-car Atkinson, Ph.D. Department of Diagnostic Radiolofir Tala University School of Medicine Sew Earan, Connecticut Diagaoatic ultrasound is an attractive sodality for the examination of soft organs such as the liver end spleen slnee it is totally nonlnvasive, causes no diacomfort and no deleterious effects have been found at diagnostic doses. Expostire to vinyl chloride monomer used in the production of FVC can lead to widespread abnormalities, an increased incidence of cancer in many sites and particularly, la associated with characteristic liver and spleen changes. Eepatotoxlcity consists of capsular fibrosis and periportal fibrosis leading to portal hypertension and splenic enlargement. Portal hypertension often results in massive fatal hemorrhage. Diagnostic ultrasound was used is a small sample of FTC workers in whom abnormalities identified by invasive techniques were confirmed, end in several patients other abnormalities were noted which had hitherto been unrecognized. A further development in ultrasound diagnostic techniques is the use of the Doppler principle to estisete blood velocity and flow, nils technique may be applied to determine the direction and volume of blood flow in the portal vein and to quantitate thereby the degree of portal vein obstruction resulting from pathological changes in the liver. 119 i } j } i i t ; f DETECTION OF LIVES AND SPLEEN PATHOLOGY AFTER VINYL -CHLORIDE EXPOSURE--POTENTIAL OF GREY-SCALE ULTRASOUND AND DOPPLER TECHNIQUES Diagnostic ultrasound has been used for many years in obstetrici and O'necolof^'. Recent improvements in technoloaf have increased the resolution to approximately 1-3 mm. and this is adequate to display the liver and. associated vasculature. Sections through the .upper abdomen using the new grey-scole ultrasound technique now reveal similar anatomical details to those which hitherto could only be observed postmortem by pathological examination. Tne transverse anatom which can be demonstrated by ultrasound is shown in Figure 1. Small subdivisions of the right brsnch of the portal vein ore seen [arrowed] and the liver consistency is well displayed. This is a prerequisite for the identification of liver end spleen changes in response to vinyl chloride exposure. One of the major visceral complications of prolonged exposure to vinyl chloride monomer (VQI) is the development of subtle pathological changes in the liver which result in obstruction to blood flow and development of hyper tension in the portal vein. One sequel of such hypertension is the develop ment of varicose veins in the lower esophagus, and 25* of patients with portal hypertension die from massive hemorrhage due to rupture of these varicose veins. In ninty percent of patients, portal hypertension is associated with cirrhosis of the liver due to alcohol abuse. Thus, tech niques to Imsge the liver substance must attempt to differentiate between alcoholic cirrhosis and VCM-relsted liver changes. Ultrasound is the only sodality which displays normal and abnormal consistencies thereby permitting this differentiation. Since portal vein obstruction results from VCM exposure, the anatomy of this system is first considered. Figure 2 shows a schematic diagram of the portal vein system which collects blood from the bowel. The vein draining the spleen is -a large structure which is Joined by the inferior mesenteric vein, receives small tributaries from the pancress, and then Joins the superior mesenteric vein to fora the portal vein posterior to the neck of the pancreas. The portal vain thereby conveys blood to the liver. A transverse ultrasound section [Figures Ja i b] shows the splenic vein receiving tributaries from the spleen, receiving the inferior mesenteric vein and Joining the superior mesenteric vein to fora the portal vein. The portal vein seen in Figure 2 passes from the region of the duodesun to the porta hepatis. At this point it lies anterior to the inferior vena cava. An ultrasonogram [Figure I] in the longitudinal plane shows the portal vein [arrowed] os a rather straight structure, which is well visualised in every patient. In patients with vinyl chloride-related liver patholo&, there is obstruction to the portal vein, and the pressure rises within It. At surgery, a large, tortuous portal vein is seen; and this is also seen on ultrasound examination [Figure 5]. The most comoon cause of portal hyper tension is cirrhosis of the liver, but the appearances of a cirrhotic liver on ultrasound examination ore different from the more localized periportal fibrosis one sees in the liver of these workers with vinyl chloride-related disease.* In VCM-exposed.workers, fibrotic changes have been described on the surface of the liver," and the dense echoes seen on the surface of the liver [arrowed in Figure 5) ore consistent with such capsular fibrosis. Bse liver substance does not appear as abnormal as that seen in a cirrhotic liver from which abnoramlly large echoes are returned with increased attenuation.7 120 When there is obatr the spleen becomes the portal venous * demonstration of a organ vhleh is difl ribs, whereas radii of mild to moderate ultrasound exaoinai in Figure 3b. The than 10 cm. A preliminary sum Fetroleum plant. Si cented, and their r examination was pet medical history, authors (K.J.W.T.) exposure history, tv^aariied here. Four patients uneq' so on ultrasound e not detected by ul~ from minor fatty i. confirmed to be ab patients were all known minimal ebon investigation, tbr assessing the valu not involve ionizi less to the patier screening. Since these prelim have evolved which The basic patholof gresslve obliterat by decreasing flow direction.1* Ultra and noninvmsive 'Soppier flowmeters moving target is other things, on dueer. --*"* the velc b: the Dopp incidenc vein (wt a pulse- ti un s xy CO Z. selectei m nitted i re the ult; that an; the sel pointin CO to (O r t0n> 3g sn time, t e region. wkfifewiiriiftT iOLOGT 3F GHE1-SCALE 2S At obstetric* end increased the resolution -play the liver end ,-pper abdomen using the _*r anatomical details ortem by pathological rmonstrated by ultresound fit branch of the portal veil displayed. This id spleen changes in 1 exposure to vinyl pathological changes in and development of hyperlertession is the develop'5J of patients vlth to rupture of these tl hypertension is il abuse, nos, t :hdifferenttate between Ult^^kid is the only inciflBereby pernitting - results from VCM ered. _n system which collects is a large structure .elves small tributaries -.terie vein to form the Zhc portal vein thereby id section [Figures 3a .*o= the. spleen. receiving ir nesenterie vein to Cion of the duodenum to 10 the inferior vena tal plane shows the portal a Is veil visualized in tted liver patbolo-, fssure rises within it. md this is also seen on cause of portal hyper,-es of a cirrhotic liver ,-e localized periportal 1 vinyl chloride-related bare been described on i on the surface of the i capsular fibrosis. The seen in a cirrhotic :d vlth increased Mat Mbfcfi-aaSaMMS JBiivI p (/) 996CVV When there is obstruction of the portal vein and portal hypertension develops, the spleen becomes passively congested since the splenic vein drains into the portal venous system. Thus, portal hypertension is suggested by the demonstration of an enlarged, congeated spleen. However* the spleen is an organ which ia difficult to assesa clinically since it is under cover of the ribs* whereas radiography of the abdomen Is also unreliable for the detection of slid to noderate splenomegaly. Spleen size can, however, be assesaed by ultraaound examination, and the spleen of a vinyl chloride worker is shown in Figure 3b. The longitudinal axis is lb u, whereas the normal is less than 10 cm. A preliminary aurvey was undertaken in.1975 of 19 workers from the British Petroleum plant, Swansea, South Wales,"* Their exposures were well docu mented, and their medical condition fully investigated. The ultrasound examination was performed without knowledge of their exposure nor of their ncdlcal history. All ultrasound examinations were carried out by one of the authors (K.J.W.T.) and results subsequently compared with their medical and exposure history. These preliminsry results have been published end are naacarized here. Four patients uaequivoeably normal after full investigation were found to be so on ultresound examination. Minimal changes in two other patients were not detected by ultrasound. Nine patients with known liver disease varying from minor fatty infiltration to established portal hypertension were all confirmed to be abnormal on ultrasound examination. The four remaining patients were all definitely abnormal on ultraaound, although only two toad known minimal changes consisting of elevated liver enzymes. On further investigation, three out of four of these abnormalities were confirmed. In assessing the value of ultrasound, it crust be recalled that this method does not involve ionizing radiation nor any other known hazard, is totally painless to the patient and is therefore a method ideally suited ftar mast screening. Since these preliminary results were reported, further technical developments have evolved which should refine the technique and increase the sensitivity. The besic pathological result of VCM liver damage appears to be the progressive obliteration of the portal vein radicles which must be accompanied by decreasing flow in the portal vein with ultimately a reversal la flow direction.* Ultrasound using the Doppler technique should be a sensitive and nonlnvasive modality to detect these changes in flow rates. Doppler flowmeters- are based on the principle that the echo reflected by a coving tasget is shifted in frequency. The amount or shift depends, amongst other things, on the velocity of the target in the direction of the transducer. Thus, if the portal vein can be demonstrated ultraaonically, then the velocity of blood flow through it can be estimated by frequency analyzing the Doppler shifts In the returning echo end correcting for the angle of incidence. In order to study only those signals originating from the portal vein (which is located close to other major vessels), it is necessary to use a pulac-Doppler flowmeter. This device is able to monitor the flow at any ' selected point on the ultrasound scan. A short burst of ultrasound is trans mitted and the returning echo is sampled after a delay which allows time for the ultrasound to travel to end from the vessel of interest. This ensures that aay Doppler shifts which are detected originate from blood moving at the selected range within a small region known as the sample volume. By pointing the transducer in a different direction and varying the range delay time, the sample volume can be positioned in any ultrasonically accessible region. 121 * ; j { ; ; j ! j t t i I | 1 [ j ! < ! { ; t < i { (i i J ! , Reliable Doppler now studies of the portal venous system can be performed by linking a pulse-Doppler flowmeter to a conventional ultrasound scanner. Such an interface has been achieved and described by one of the authors (P.A.). A long section of the vessel is identified on the ultrasound scan and then the machine switched to the Doppler mode. The sane transducer is used for both nodes of operation. The sample volume is marked by a bright-up cursor on the 5--scan [arrowed in Figure U], and is maneuvered into the lumen of tbe portal vein. The Doppler signals from this point are monitored and frequency analyzed to determine the velocity flow components. If required, voli=e flow rate can be estimated by measuring the calibre of tbe vessel and tbe angle of the ultrasound beam. During a preliminary evaluation of the technique, the volume flow is a series of five normal subjects vas. found to lie within tbe commonly accepted range of values. This study also revealed that the mean velocity through tbe portal vein vas similar to that through the inferior vena cava, the difference in volume flows being accommodated by differences in the calibre of the two vessels. The Doppler information will be improved by including a direction-sensing facility which la currently under construction. This viU allow recognition of the large reverse flow which can occur in advanced stages of portal hypertension. In conclusion, ultrasound is a safe, noninvasive modality which permits the display of the portal vein and spleen together with the characteristic cbsnges associated with portal hypertension. The display of tbe liver consistency should permit differentiation from cirrhosis. The addition of blood-velocity monitoring by Doppler should increase the sensitivity of ultrasound for tbe detection of VQt-related liver disease. REFERESCE5 1. K. J. V. Taylor, D. A. Carpenter and T. R. McCready, "Grey-scale echography in the diagnosis of intrabepatie disease," J. Clin. Ultrasound. i:26L-7 (1973). 2. E. H. Carlsec and R. A. Filly, "Sewer ultrasonographic anatomy in the upper abdomen: I. The portal and hepatic venous snatony," J. din. Ultrasound. 1:83-90 (1976). 3. R. A. Filly sad E. I. Carlsen, "Sewer ultrasonographic anatomy in tbe upper abdomen; XX. Tbe major systemic veins and arteries with a special note on localization of the pancreas," J. Clin. Ultrascund. b:91-96 (1976). k. J. L. Creech and L. Kakk, "Diver disease among polyvinyl chloride production workers," Ann. S.T. Acad. Sci.. 2b6:B8-9^ (1975)* 3. K. J. V. Taylor, J. J. Barrett, D. M. J. Williams, F. X. Smith and B, V. Duck, "Preliminary results of grey-scale ultrasonography in the detection of vinyl chloride related liver and spleen disease," Froc. Royal Soc. Med.. 69:292-295 (1976). 6. H. J. Karsteller, V. K. Lelbach, R. Muller and F. Gedigt, "Unusual splenomegalic liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production vorkera," Ann- H.Y. Acad. Sci.. 2i*6:95-13fc (1975). K. J. V. Taylor, "Grey-scale ulti Radiology. 119; l 8. K. J. V. Taylor, scale ultraaonoi agents," The Lac 9. D. M. J. Villias 3. V. Duck, "Mot workers by grey(1976). U. P. Atkinson, "Os Ph.D. Thesis, Ui 30 0 CO CO CD Cl -J Liver 2cr R. branch of portal vein Hepatie artery inferior vena cava Figure 1. T> tl v; - ; -- ' ,r- tf- 1`- - '// ; * .. V "*:nr m *. :v ^ *-, *' . : - ..vL -' ,, VTW. ' . ' " _'j J- '- * - "~Zs : ~ T` ^ ^ zzJr"- m UK s system can be performed lonal ultrasound scanner. . by one of the authors led on the ultrasound seen . The sane transducer Is uae is narIced by a bright-17 s maneuvered Into the on this point are oonitored flov components. If asurlng the calibre of the , the volwse flov in a rithin the eomonly accepted -he aean velocity- through nferior vena cava, the differences in the eslibre 1 be Improved by incluriltg mder construction. This which esn occur in advanced modality which permits the 1th the characteristic e display of the liver irrhf^^. The addition nerJ^Ptbe sensitivity of r disease. 'cCready, "Grey-scale disease," J. Clin. sonographic anatomy In the mous anatomy," J, Clin. lonographlc anatomy in the t and arteries with a special Lin. Ultrasound, b:91-96 (197: nog polyvinyl chloride 21.6:88-91* (1975). lliams, P. M. Smith end ale ultrasonography in the nd spleen dieeese," Proc. and F. Gedlgk, "Unusual peritoneoscopy and guided ction workers," ann. s.Y. 7. K. J. tf. Saylor, D. A. Carpenter, V. R. McCreedy end C* R. Hill, "Grey--scale ultresound imaging: the anatomy and pathology of the liver," Radiology. 119:^15-1*23 (1976). 8. K. J. tf. Taylor, S. H. S. Villi ana, P. M. Smith and B. tf. Duek,*Grey- scale ultrasonography for monitoring industrial exposure to hepato--toxic agents," She lancet. 1, 1222 (1975)- 9. 0. K. J. Villisms, F. M. Smith, K. J. V. Saylor, I. R. Crossley and B. V. Dude, "Monitoring liver disorders in vinyl chloride monomer workers by grey--scale ultrasonography,* Brit. J. Indust. Med. 33:152--157 (1976). 10. P. Atkinson, "On the neesureaient of blood flov by ultrasound," Fh.D. Thesis, University of Bristol, Bristol, England (1975)* Figure 1. Transverse ultrasound scan through the abdomen shoving the great vessels and their small subdivisions. Vessels with lumens less than 1* mm are very veil visualired. 123 R&S 113968 - 11 I--II 11-11 men figure 2. Schema, of upper abdominal organs and Tessels to abow portal vein formed by junction of splenic vein and superior mesenteric vein seen in plane A-A. Hie portal vein so formed passes upwards in front of the inferior vena cava [VC] into the liver in the plane marked S-S. A is aorta* LK and RK are left and right kidneys and GB is gallbladder, the level of the second lumbar vertebra [12] is marked. Figure 3a. Figure 3b. Transverse ultrasound scan through liver in plane indicated by line A-A on Figure 2 showing splenic vein [arrowed] Joining superior mesenteric vein to form portal vein [P]. The aorta [A] is seen posteriorly. Longitudinal section through an enlarged spleen in the plane A-A of Figure 2. The splenic vein [V] is seen leaving the hilus of the spleen. The spleen la limited above by the left side of the diaphragm [D]. id vessels to ihov portal rein aad superior Iha^ktal rein so he ^HVior rena cars *rkeA is aorta, 's and G3 Is gallbladder, -ebra [lZ] is narked. liver in plane indicated iesie vein [arroved] o fore portal vein [Pj. Larged spleen in the ~ vein [Y] is seen leaving vn is United above by the i Figure k. Longitudinal section through liver aad great vessels in. plane S-B in Figure 2. The inferior vena cava [VC] is seen posteriorly. The portal vein (?] extends upwards from its formation into the liver substance [L] An electronic cursor [arroved] can he moved into the portal vein to locate the source of Doppler flov information. E 30 </> CO to -1 o I Figure 5. Longitudinal scan of portal vein [P] passing into liver substance. The portal vein is enlarged and highly tortuous consistent vith portal hypertension in a patient vith VQt exposure. In addition, multiple echoes appear as thick vhite lines on the surface of the liver [arroved]. This is consistent vith capsular fibrosis. 125 I *t \ l vf r-* C \ i t R&S 113971 STzcudjz camtsma oxt TOXIC SUBSTAHCES IN THE AIR EHVIRONferr ZDITP XT THE m POLLUTIOK COKTKDL 45SOCUIIOH SPONSORED XT THE KQ EMGLABD SEOKW sad THE TiannaiL COOHOL of Ot m pouutioh corixol AssociAno* November 7-9, 1976 lyitt Isjsncy Cmbtldg* Cambridge, Massachusetts TABLE OF CONTENTS Keynote Address John D. Spongier Toxic Substance* Legislation Opening A Closing Remarks John A. S. McClcnnon A Review of the Federal Toxic Substances Legislation Kenneth Olsen The Toxic Substances Control Act: Will it be a Net for Whales or a Net for Minnow*? E. 8. Blair Toxic Substance* Legislation - Research Respondent S. D. Murphy Toxic Substances Control Act: Legal Response David Schoenbrod An Administrative Response to TSCA Merrill S. Holman Progress in s Commit? Arsenic Stud? Cenevieve M. Hetanoskl Serve Conduction Velocity Tests in Smelter Workers Robert C. Feldman Csneer Among Arsenic Exposed Workers is a Copper Saelter Philip E. Interline Arsenic Absorption is Children Hear Copper Smelters NAS Report on Arsenic: A Critique Edward L. Raker manual Araenie Measurement Difficulties sad Sophistication in Atmospheric Monitoring Thanes A. Hinner* 1 3 6 13 18 21 28 31 A2 A8 57 5 78 Health Effect* of Expo* Commit? An Epidemiology Deserip of the Liver A Commit? Vinyl Chlor Birth Defects Associate Defects of IJ---------- A sp Exposure--P< 0f Doppler Teel Sew Applied X fi CO >gy rvc Manufec _ Personal A1 Risk Assess CO (O T Mo; -vl CO Ena: Chemical Characterised: fron Emerging Fossil Fu< Toxicology of Fossil Fui N-Rltrosamines in the A; Overview of Conference Subject Index viu